European guidelines for the diagnosis and treatment of pancreatic exocrine insufficiency: UEG, EPC, EDS, ESPEN, ESPGHAN, ESDO, and ESPCG evidence‐based recommendations

Received: 23 May 2024 - Accepted: 12 August 2024 DOI: 10.1002/ueg2.12674 GUIDELINE European guidelines for the diagnosis and treatment of pancreatic exocrine insufficiency: UEG, EPC, EDS, ESPEN, ESPGHAN, ESDO, and ESPCG evidence‐based recommendations J. Enrique Dominguez‐Muñoz 1 |Miroslav Vujasinovic 2 |Daniel de la Iglesia 3 | Djuna Cahen 4 |Gabriele Capurso 5 |Natalya Gubergrits 6 |Peter Hegyi 7,8,9,10 | Pali Hungin 11 |Johann Ockenga 12 |Salvatore Paiella 13 |Lukas Perkhofer 14 | Vinciane Rebours 15 |Jonas Rosendahl 16 |Roberto Salvia 13 |Isabelle Scheers 17 | Andrea Szentesi 8 |Stefanos Bonovas 18,19 |Daniele Piovani 18,19 | J. Matthias Löhr 20 |on behalf of the European PEI Multidisciplinary Group 1 Department of Gastroenterology and Hepatology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain 2 Department of Medicine, Karolinska Institutet and Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden 3 Department of Gastroenterology, University Hospital Puerta de Hierro, Madrid, Spain 4 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands 5 Department of Gastroenterology, San Raffaele University Hospital, Milan, Italy 6 Into‐Sana Multi‐Field Clinic, Odesa, Ukraine 7 Centre for Translational Medicine, Semmelweis University, Budapest, Hungary 8 Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary 9 Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary 10 Translational Pancreatology Research Group, Interdisciplinary Center of Excellence for Research and Development and Innovation, University of Szeged, Szeged, Hungary 11 Faculty of Medical Sciences, Newcastle University, Newcastle‐upon‐Tyne, UK 12 Department of Gastroenterology, Endocrinology and Clinical Nutrition, Klinikum Bremen Mitte, Bremen, Germany 13 Unit of Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy 14 Department of Internal Medicine I, Section of Interdisciplinary Pancreatology, Ulm University Hospital, Ulm, Germany 15 Department of Pancreatology, Beaujon Hospital, DMU Digest, AP‐HP, Clichy, France 16 Department of Internal Medicine I, Martin Luther University, Halle, Germany 17 Pediatric Gastroenterology, Hepatology and Nutrition Unit, Cliniques Universitaires Saint‐Luc, Université Catholique de Louvain, Brussels, Belgium 18 Department of Biomedical Sciences, Humanitas University, Milan, Italy 19 IRCCS Humanitas Research Hospital, Milan, Italy 20 Department of Clinical Sciences, Karolinska Institutet and Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. © 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology. United European Gastroenterol J. 2024;1–48. wileyonlinelibrary.com/journal/ueg2 - 1 Correspondence J. Enrique Dominguez‐Muñoz, Department of Gastroenterology and Hepatology, University Hospital of Santiago de Compostela, Choupanna s/n, Santiago de Compostela 15706, Spain. Email: [email protected] Funding information United European Gastroenterology, Grant/ Award Number: Grant number unknown Abstract Pancreatic exocrine insufficiency (PEI) is defined as a reduction in pancreatic exocrine secretion below the level that allows the normal digestion of nutrients. Pancreatic disease and surgery are the main causes of PEI. However, other conditions and upper gastrointestinal surgery can also affect the digestive function of the pancreas. PEI can cause symptoms of nutritional malabsorption and deficiencies, which affect the quality of life and increase morbidity and mortality. These guidelines were developed following the United European Gastroenterology framework for the development of high‐quality clinical guidelines. After a systematic literature review, the evidence was evaluated according to the Oxford Center for Evidence‐Based Medicine and the Grading of Recommendations Assessment, Development, and Evaluation methodology, as appropriate. Statements and comments were developed by the working groups and voted on using the Delphi method. The diagnosis of PEI should be based on a global assessment of symptoms, nutritional status, and a pancreatic secretion test. Pancreatic enzyme replacement therapy (PERT), together with dietary advice and support, are the cornerstones of PEI therapy. PERT is indicated in patients with PEI that is secondary to pancreatic disease, pancreatic surgery, or other metabolic or gastroenterological conditions. Specific recommendations concerning the management of PEI under various clinical conditions are provided based on evidence and expert opinions. This evidence‐based guideline summarizes the prevalence, clinical impact, and general diagnostic and therapeutic approaches for PEI, as well as the specifics of PEI in different clinical conditions. Finally, the unmet needs for future research are discussed. KEYWORDS cystic fibrosis, diabetes, diagnosis, fecal elastase, guidelines, malnutrition, pancreatectomy, pancreatic cancer, pancreatic enzyme replacement therapy, pancreatic exocrine insufficiency, pancreatitis, steatorrhea, treatment, weight loss INTRODUCTION Pancreatic exocrine insufficiency (PEI) has long been thought to be the result of a secretory deficiency of enzymes and/or bicarbonates from the pancreas. 1 As a result, PEI has been observed almost exclusively in the context of pancreatic diseases, primarily chronic pancreatitis (CP) and cystic fibrosis (CF) and later in pancreatic cancer (PC) or after resective pancreatic surgery. Accordingly, guidelines addressing PEI have focused almost exclusively on these four conditions. The first evidence‐based guidelines using the Oxford or Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) systems to address PEI in the context of CP were published in 2012 2 (Figure 1). Following an award from the United European Gastroenterology (UEG), 28 the first European guidelines were developed and publishedin2017. 24 Ithasrecentlybeennotedthatthereisapaucityof research on PEI in the general population and in patients with non‐ pancreatic diseases, 29 although the number of relevant publications is increasing. 30 Two interrelated issues have emerged about PEI. Pancreatic exocrine insufficiency must be considered a maldigestion syndrome rather than an isolated organ defect. As a consequence, the diagnosis and treatment of PEI must go beyond the pancreas and require a more holistic view, which has led to a new definition of PEI (Chapter 1). In this guideline, we have reviewed many other conditions of PEI, some of which have anatomically intact pancreas but impaired intraluminal pancreatic enzyme activity. For “normal” digestion, food and pancreatic enzymes must meet at the right time, place, and environment. 31 In addition to the need for a revised definition of PEI and increased awareness of this condition in some pancreatic and extrapancreatic diseases, the considerable variability in diagnostic and therapeutic approaches to PEI in different clinical scenarios and centers across 2 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Europe and non‐European countries has been identified as an unmet need that justifies the development of this guideline. We also found a lack of high‐quality prospective clinical trials in many areas of PEI (Figure 2). These new UEG guidelines are therefore unique but can only be seen as the first attempt in this direction. METHODS The UEG framework for the development of high‐quality clinical guidelines, as proposed by the UEG Quality of Care Taskforce, was adhered to throughout the guideline's development. 32 FIGURE 1 Overview of the various guidelines and consensus recommendations for CP (above) and PEI (below) referring to the following: American College of Gastroenterology (ACG) 3 ; American Gastroenterological Association (AGA) 4 ; American Pancreatic Association (APA) 5 ; Australia 6–8 ; Belgium 9 ; Canada 10 ; Cochrane 11 ; German Society for Digestive and Metabolic Diseases (DGVS) 12 ; Hungary 13 ; Italy 14,15 ; Japan Pancreas Society (JPS) 16 ; Poland 17 ; Russia 18,19 ; Spain 20,21 ; South Africa 22 ; Turkey 23 ; United European Gastroenterology (UEG) 24 ; Romania 25 ; Sweden 26 ; United Kingdom. 27 CP, chronic pancreatitis; PEI, pancreatic exocrine insufficiency. FIGURE 2 Unmet needs, lacking scientific evidence, and future directions. DOMINGUEZ‐MUÑOZ ET AL. - 3 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Scope and purpose In addition to defining the general concept, mechanisms, and consequences of PEI, this guideline aims to provide evidence‐based recommendations for the general diagnosis and treatment of PEI in clinical practice. It also addresses the specificity of PEI under various pancreatic and extrapancreatic diseases and conditions. The primary health objectives of this guideline include accurate diagnosis, optimal treatment strategies, and prevention of complications. By following these guidelines, healthcare professionals will be able to better increase the quality of life (QoL), minimize symptoms, and improve overall outcomes in their patients. Steering Committee and supporting societies Members of the Steering Committee were selected based on their expertise in the field, ability to contribute to the work process, and personal experience as effective team members. 32 They were familiar with the methodology of several previous guidelines 12,24,33 and their evaluations. 34 On behalf of the European Pancreatic Club (EPC), four EPC members (lead, co‐chair, and scientific secretaries) constitute the Steering Committee responsible for the design of the guideline protocolandtheUEGapplication.TheSteeringGroup consulted experts in methodology and research synthesis who were actively involved in all stages of the process. The EPC invited other UEG Specialist Member Societies to join this project with the aim of developing transversal multidisciplinary guidelines to be adopted by all specialties in Europe. The following societies confirmed their participation: the European Digestive Surgery (EDS), European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), European Society for Clinical Nutrition and Metabolism (ESPEN), European Society of Digestive Oncology (ESDO), and European Society of Primary Care Gastroenterology (ESPCG). Several UEG National Member Societies and Patient Associations endorsed this proposal. The UEG provided both endorsement and financial support for the development of the guidelines. Working groups The Steering Committee, in collaboration with the other participating societies, designated Working Group (WG) representatives for the different topics within the guideline's scope and invited experts from a range of medical specialties to contribute to them. Conflict of interest (COI) forms were distributed to all participants, and signed scanned copies were sent to the UEG headquarters in Vienna in accordance with the UEG rules. A request was made to all of the participants for updated COIs to be provided at 6‐month intervals over the duration of the working process. The first meeting of the group was held during the UEG Week in Vienna, Austria (October 2022). The WGs were finalized, and a leader responsible for each group was appointed (Table 1). Definition of search questions (PICO) Following the meeting in Vienna, the WGs commenced the formulation of the questions in accordance with the recommendations set forth by the Steering Committee (Appendix 1). These questions were subsequently endorsed by the entire group. In order to incorporate the patient perspective, questions were shared with patient associations. The PC Europe (PCE), the Swedish patient organization PALEMA, and the German “Arbeitskreis der Pankreatektomierten” (AdP) were engaged as organizations representing patients to provide their feedback on the drafted PICO questions (see acknowledgments section). Search for scientific evidence A comprehensive search for scientific evidence was performed across the MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trial databases. The search strategy used for each chapter is outlined in Appendix 1. A stepwise approach was used to include studies as follows: systematic reviews and meta‐analyses, randomized controlled clinical trials, case‐control studies, observational cross‐ sectional and longitudinal cohort studies, and other types of evidence. The following studies were considered eligible for inclusion: studies of PEI associated with any pancreatic or extrapancreatic disease or condition, including patients of any age, conducted in any country, and published in full text in English in peer‐reviewed journals. The following studies were excluded: narrative reviews, editorials, abstracts or letters; those published in non‐peer‐reviewed journals; in TABLE 1Overview of the working groups. 1. Concept, pathogenesis, and clinical relevance 2. A general diagnostic approach to PEI 3. A general therapeutic approach to PEI 4. PEI secondary to CP 5. PEI after acute pancreatitis (AP) 6. PEI associated with PC 7. PEI secondary to CF 8. PEI after pancreatic surgery 9. PEI after esophageal, gastric, and bariatric surgery 10. PEI in patients with type 1 and type 2 diabetes 11. PEI in other conditions Abbreviations: CF, cystic fibrosis; CP, chronic pancreatitis; PC, pancreatic cancer; PEI, pancreatic exocrine insufficiency. 4 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License vitro and animal experimental studies; and studies published in languages other than English. Grade quality of evidence, and definition of statements and comments In light of the available evidence, statements were formulated in order to address these questions. The statement format included the question, statement and levelof evidence. The statementswere followed by qualifyingcomments written byeach WG andreviewed by theSteering Committee. Relevant comments and suggestions from the global consensus group were also considered. Statementswere formulated in the context of population/problem, intervention, comparison, and outcome (PICO) questions 35 where applicable (see Appendix 1). The quality of evidence was appraised according to the Oxford Center for Evidence‐Based Medicine system 32,36 and the GRADE system. 37 The WGs were supported by two expert methodologists throughout the process of searching, selecting, and evaluating the scientific evidence as well as writing the statements. The methodologists also provided training in basic guideline methodology, advised during the development process, and reviewed the draft guideline manuscript. Consensus process All questions, statements, and related comments were uploaded to a designated platform and subjected to a repeated Delphi process for all of the participants in the Guideline Consortium. It was requested that members of the WGs provide updates on any potential conflicts of interest on a regular basis (see Appendix 2). In the event of a clear COI, members were obliged to abstain from voting on the specific topic in question. A secretary provided comprehensive assistance throughout the entirety of the working process. A level of agreement of 80% or higher was deemed to be indicative ofconsensus. Statements with less than 80%agreement werereturned to the WG for further consideration. Updated versions were discussed at the EPC meeting in Alpbach, Austria (June 2023), including a round of Test and Evaluation Directorate (TED) voting in accordance with the previously described methodology, until an agreement was reached. 24,33 The degree of consensus was indicated alongside the level of evidence for each of the statements included in the guideline. In accordance with the consensus reached at EPC 2023, and following a final round of adjustments, the initial draft of the manuscript was prepared and distributed to the WG coordinators and methodologists for their comments. The resulting guidelines were then collated and sent to independent non‐European expert pancreatologists representing the Japanese Pancreas Society, the Korean Biliopancreatic Association, and the Latin American Pancreatic Study Group for review and comments (see Acknowledgments). A final round of adjustments was then made. The key concepts and recommendations of the guidelines are highlighted in Figure 3. CHAPTER 1: CONCEPT, PATHOGENESIS, AND CLINICAL RELEVANCE OF PEI What is the definition of PEI? Statement 1.1 PEI is defined as a reduction in the exocrine pancreatic secretion and/or intraluminal activity of pancreatic enzymes below the level that allows normal digestion of nutrients. PEI is associated with the malabsorption of nutrients and may result in intestinal symptoms and/or nutritional deficiencies. Consensus;Percentage of agreement:97.4% Comment: Failure of the exocrine pancreas to deliver the required levels of enzymes to the intestinal lumen for normal nutrient digestion is the main factor defining PEI. 24,27,38 However, the clinical manifestation of PEI is variably influenced by other relevant factors; therefore, the threshold for the clinical manifestation of PEI varies among patients. The concept of PEI implies that pancreatic enzyme replacement therapy (PERT) can restore the digestion and absorption of nutrients. What are the mechanisms leading to PEI? Statement 1.2 The mechanisms leading to PEI primarily include the reduced secretion of pancreatic enzymes and bicarbonates due to pancreatic disease or insufficient postprandial stimulation of the exocrine pancreas. Level of evidence:1;Percentage of agreement:97.6% Comment: Decreased pancreatic enzyme secretion is the primary mechanism of PEI. Common causesof decreased secretion include loss of functional exocrine pancreatic tissue, such as in CP, CF, necrotizing pancreatitis, or pancreatic resection, and pancreatic ductal obstruction, such as in PC. 39–42 Reduced postprandial vagal (autonomic nerve division) and hormonal (low cholecystokinin [CCK] and secretin release) stimulation of pancreatic secretion is an additional factor that leads to PEI in patients after pancreaticoduodenectomy, gastrectomy, or gastric bypass. 43–46 What is the impact of factors other than pancreatic secretion on PEI? Statement 1.3 Factors other than pancreatic secretion, mainly gastrointestinal anatomy and intraluminal pH, also play important roles in the clinical manifestations of PEI. Level of evidence:3;Percentage of agreement:97.6% DOMINGUEZ‐MUÑOZ ET AL. - 5 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License FIGURE 3 Key general concepts and recommendations. PEI, pancreatic exocrine insufficiency; PERT, pancreatic enzyme replacement therapy. PRO, Patient reported outcome. Comment: The clinical manifestation of PEI is influenced by several factors, including gastrointestinal anatomy, intraluminal pH, compensatory activity of non‐pancreatic digestive enzymes, bowel function, dietary habits, and nutritional requirements. 38,43,44 In addition to the altered vagal and hormonal postprandial stimulation of pancreatic secretion, changes in the upper gastrointestinal tract due to surgery may affect intraluminal protease activation (low intestinal endopeptidase secretion) and the mixing of pancreatic enzymes with chyme. The digestive activity of secreted pancreatic enzymes depends on the intraluminal pH, and pancreatic enzymes are inactivated at pH values below 4. Salivary amylase, gastric pepsin and lipase, and intestinal disaccharidases and peptidases partially compensate for pancreatic maldigestion. Bowel function, dietary habits, and nutritional requirements may influence the development of symptoms and nutritional deficiencies. What are the consequences and clinical relevance of PEI? Statement 1.4 Regardless of the cause of PEI, intestinal symptoms and nutritional deficiencies are the main clinical manifestations and consequences of PEI, which can affect the QoL and increase the risk of long‐term malnutrition‐related complications. Level of evidence:1;Percentage of agreement:97.6% Comment: Intestinal symptoms associated with PEI include diarrhea, steatorrhea, bloating, abdominal cramps, and flatulence. 47 Nutritional deficiencies typically include protein, fat‐soluble vitamins, and other micronutrient deficiencies associated with weight loss, osteoporosis, and sarcopenia. 47–49 Patients with PEI are also prone to small intestinal bacterial overgrowth and other significant dysbioses of the gut microbiome. 50–52 Due to various factors that may influence the threshold and type of clinical manifestations of PEI, there is high variability in the symptoms and nutritional consequences of PEI among patients. 47 Therefore, PEI has a variable impact on the QoL and long‐ term complications in different patients. CHAPTER 2: A GENERAL DIAGNOSTIC APPROACH TO PEI When is a diagnostic work‐up for the detection of PEI indicated? Statement 2.1 Diagnostic work‐up for PEI is indicated in the presence of pre‐existing high‐risk conditions such as CF, CP, acute necrotizing pancreatitis, PC, or previous pancreatic surgery. PEI may also be considered in the 6 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License differential diagnosis of patients with symptoms suggestive of maldigestion and malabsorption, such as steatorrhea or chronic diarrhea. Level of evidence:3;Percentage of agreement:97.0% Comment: Several pancreatic conditions warrant a diagnostic work‐up to identify PEI due to a high pre‐test probability. 8,27,53–55 Additionally, the diagnosis of PEI should be considered in the differential diagnosis of steatorrhea or chronic diarrhea, suggesting maldigestion and malabsorption of nutrients. 56 How can PEI be diagnosed? Statement 2.2.1 In general, the diagnosis of PEI should be based on a combined assessment of symptoms, nutritional status, and pancreatic function in an appropriate clinical context. Level of evidence:3;Percentage of agreement:97.3% Statement 2.2.2 Confirmation of PEI may not always require pancreatic function tests in patients with a high likelihood of PEI, such as those with pancreatic head cancer or those who have undergone pancreaticoduodenectomy or total pancreatectomy. Level of evidence:2;Percentage of agreement:97.3% Comments: Due to their limited specificity, PEI cannot be diagnosed solely based on commonly available pancreatic function tests. 57,58 Symptoms and nutritional deficiencies are not specific to PEI. 47 Therefore, a combined assessment of the symptoms, nutritional status, and pancreatic function in each pertinent clinical context may be appropriate for diagnosing PEI in clinical practice. The likelihood of PEI in patients with pancreatic head cancer and in those who have undergone total pancreatectomy or pancreaticoduodenectomy is greater than 90%. 41,59,60 In such cases, PERT can be initiated after assessing symptoms and nutritional status, and pancreatic function evaluation (e.g., with fecal elastase [FE‐1]) can be avoided. What is the role of symptoms in the diagnosis of PEI? Statement 2.3 In patients with pancreatic disease or a history of previous pancreatic surgery, the diagnosis of PEI is supported by the presence of symptoms of malabsorption. However, these symptoms are neither sensitive nor specific to PEI, and additional nutritional evaluation and pancreatic function testing may be required. Level of evidence:3;Percentage of agreement:94.7% Comments: The symptoms commonly associated with PEI include steatorrhea, voluminous and foul‐smelling stools, diarrhea, flatulence, bloating, abdominal discomfort, and weight loss. In clinical studies on patients with confirmed PEI secondary to different pancreatic diseases, the frequency of clinically evident steatorrhea ranged 15%– 70%, and the frequency of flatulence ranged 55%–100%. 47 PEI can be diagnosed if clinically evident steatorrhea is present in patients with known pancreatic disease or history of pancreatic surgery. 61 However, owing to the low specificity of the symptoms, nutritional evaluation and pancreatic function testing should be strongly considered to support the diagnosis of PEI. Diagnosis of PEI in patients with an undiagnosed pancreatic disease or history of pancreatic surgery can be challenging because of the nonspecific nature of PEI symptoms. What is the role of nutritional assessment in the diagnosis of PEI, and what methods can be used to assess the nutritional status of these patients? Statement 2.4.1 Patients with PEI often have nutritional deficiencies, and nutritional assessment can aid in the diagnosis of PEI in patients with pancreatic disease or a history of pancreatic surgery. Level of evidence:3;Percentage of agreement:97.0% Statement 2.4.2 The nutritional status of patients with PEI is evaluated primarily using anthropometric parameters. If malnutrition is suspected, blood parameters of malnutrition should be assessed. Level of evidence:3;Percentage of agreement:95.5% Comment: There is limited evidence to support the use of nutritional markers for diagnosing PEI due to the lack of an appropriate reference method. Single assessments of body weight, body mass index, weight loss, lean body mass, and muscle mass are not sensitive enough for diagnosing PEI. Serial readings are more useful in this context. Limited evidence suggests that serum levels of fat‐soluble vitamins, trace elements such as magnesium, selenium and zinc, and plasma proteins, including retinol binding protein, albumin, and pre‐ albumin, may have diagnostic utility in PEI. 62–73 However, strong recommendations cannot be made due to the limited evidence. How can exocrine pancreatic function be evaluated? Statement 2.5 The exocrine pancreatic function can be evaluated through direct invasive tests that measure the stimulated pancreatic secretion in DOMINGUEZ‐MUÑOZ ET AL. - 7 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License duodenal fluid or non‐invasive tests that quantify fecal pancreatic enzymes. Indirect non‐invasive tests can be used to evaluate the effect of pancreatic enzyme deficiency on digestion. Level of evidence:3;Percentage of agreement:98.5% Comment: Pancreatic secretion can be accurately evaluated by bicarbonate and enzyme quantification in the duodenal fluid after intravenous administration of secretin and CCK. Duodenal contents can be obtained using a nasoduodenal tube or endoscope. 74,75 However, this test is invasive and cumbersome and is rarely used in clinical practice. An alternative method for quantifying pancreatic secretion is to measure the FE‐1 concentration. This test is frequently used in clinical practice. However, its accuracy for PEI is low mainly because of its low levels of specificity and positive predictive value. 58,76 Non‐invasive digestion tests are available, including quantification of the coefficient of fat absorption (CFA) after a 72‐h stool collection with the patient on a standardized 100 g fat diet and the 13C‐mixed triglyceride (MTG) breath test. Both tests evaluate the digestive function of the pancreas; however, false‐positive results may occur in patients with other causes of maldigestion and fat malabsorption. 77,78 What is the role of direct invasive tests in the diagnosis of PEI? Statement 2.6 Direct pancreatic function tests should not be used for the diagnosis of PEI in clinical practice. Level of evidence:3;Percentage of agreement:100% Comment: Direct invasive tests accurately evaluate stimulated pancreatic secretion but do not assess the ability of secreted enzymes to digest ingested food. Therefore, in accordance with the definition of PEI, direct invasive tests are not applicable. What is the role of non‐invasive tests for the diagnosis of PEI? Statement 2.7 Non‐invasive tests such as FE‐1 and 13C‐MTG breath tests are recommended for assessing pancreatic exocrine function in clinical practice. Level of evidence:2;Percentage of agreement:98.5% Comment: The FE‐1 test is commonly used as a non‐invasive pancreatic function test. This test is widely available and requires only a small amount of stool sample for analysis. It is generally accepted that the lower the FE‐1 concentration, the higher the probability of PEI. However, a cut‐off for PEI cannot be established, although a threshold of 200 μg/g is frequently used. 58 The test is at risk of producing false‐positive results in individuals with a low pre‐ test probability and false‐negative results in those with a high pre‐ test probability. Whenever possible, the FE‐1 concentration should be measured in a formed stool sample to reduce the rate of false positive results. The diagnosis of steatorrhea traditionally involves the quantification of CFA. However, this test is cumbersome and unpleasant and cannot differentiate between steatorrhea caused by PEI and other causes of fat malabsorption. The 13C‐MTG breath test is considered a suitable alternative to CFA for diagnosing PEI and evaluating the effectiveness of PERT in clinical practice. 78,79 However, this test is not widely available and may produce false‐positive results in patients with non‐pancreatic causes of fat malabsorption. What is the role of radiological imaging in the diagnosis of PEI? Statement 2.8 PEI cannot be diagnosed using radiological imaging. Level of evidence:4;Percentage of agreement:98.5% Comment: Imaging with computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography is not used to diagnose PEI but is often used in patients with confirmed or suspected PEI to determine the underlying causes. However, secretin‐enhanced magnetic resonance cholangiopancreatography (s‐MRCP) can qualitatively and quantitatively assess pancreatic exocrine fluid secretion. 80,81 The clinical use of s‐MRCP is limited due to the lack of availability of secretin in many countries. Can the clinical response to PERT be used to diagnose PEI? Statement 2.9 If the diagnosis of PEI cannot be established based on the combined evaluation of symptoms, nutritional status, and pancreatic function, assessing the clinical response to empirical PERT may be useful in the appropriate clinical context. Level of evidence:5;Percentage of agreement:97.3% Comments: Diagnosing PEI can be challenging in some cases owing to the low specificity of symptoms and nutritional deficiencies as well as the limited accuracy of the FE‐I test. Therefore, in patients with confirmed pancreatic disease, the evaluation of the clinical response to PERT in terms of symptom relief and nutritional improvement may support the diagnosis of PEI. However, evidence supporting this approach is lacking. 8 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License CHAPTER 3: A GENERAL THERAPEUTIC APPROACH TO PEI What are the general indications for the treatment of patients with PEI? Statement 3.1.1 PEI should always be treated. Level of evidence:1;Percentage of agreement:98.8% Statement 3.1.2 PERT is indicated in patients with PEI secondary to CP, AP, PC, CF, history of pancreatic surgery, and possibly other metabolic or gastroenterological conditions. Level of evidence:1;Percentage of agreement:90.3% Comment: PERT should be provided to all patients diagnosed with PEI in agreement with PEI definition and the guidelines for CP. 24,82 PEI results in symptoms and nutritional deficiencies owing to maldigestion, malabsorption, and impaired nutrient metabolism. 83–85 Fat and protein absorptions increase significantly with PERT compared with baseline or placebo. 86 Further studies are needed to evaluate the long‐term effects of PERT on the morbidity and mortality in patients with PEI. What are the general benefits of PERT in patients with PEI? Statement 3.2.1 PERT enhances fat and protein absorption in patients with PEI. Level of evidence:1;Percentage of agreement:96.4% Statement 3.2.2 PERT positively affects body weight, nutritional status, symptoms, and the QoL in patients with PEI. Level of evidence:1;Percentage of agreement:98.8% Statement 3.2.3 PERT may reduce morbidity and mortality in patients with PEI. Level of evidence:3;Percentage of agreement:90.4% Comment: Two meta‐analyses on PEI secondary to CP reported that PERT decreases fecal fat excretion and improves the CFA and nitrogen absorption compared with baseline and placebo. 39,86 PERT reduces weight loss after AP 87 , improves body weight, nutritional status, and the QoL in patients with CP 88–90 , and improves body weight and symptoms of maldigestion in patients with PC. 39,41 No randomized clinical trials with sufficiently long durations have evaluated the effect of PERT on the morbidity and mortality of patients with PEI. However, because malnutrition is the primary clinical consequence of PEI and has been linked to poor outcomes in various PEI‐related diseases, it is reasonable to consider PERT as a treatment for preventing PEI‐related morbidity and mortality. 41,91–93 What enzyme preparations can be used for the treatment of patients with PEI? Statement 3.3.1 Pancreatic enzyme preparations, particularly pancreatin, are the recommended first‐line treatment for PEI. Level of evidence:1;Percentage of agreement:98.8% Statement 3.3.2 Small‐sized enteric‐coated pellets are the preferred pancreatin preparations for PEI. Level of evidence:2;Percentage of agreement:98.8% Statement 3.3.3 The most commonly used PERT preparations are of porcine origin. Patients should be informed of the porcine origin of PERT before initiating therapy. Level of evidence:5;Percentage of agreement:95.2% Comment: PERT is available in different preparations that vary in their lipase, amylase, and protease content. These preparations are labeled according to their lipase activity. 94–96 PERT preparations should mix well with chyme, resist inactivation by gastric juices, empty from the stomach with nutrients, and release enzymes rapidly in the proximal small intestine. 95,97 The particle size and size distribution of pancreatic enzyme preparation pellets have implications for their clinical efficacy. 98–100 Particles smaller than 2 mm may facilitate better dispersal and simultaneous emptying with chyme from the stomach to the duodenum. 24,94,101–104 Importantly, pancreatic enzyme preparations are pH sensitive. The enzymes are protected from gastric acidity by enteric coating, which disintegrates rapidly at pH ≥5.5, in the duodenum to release them. 94,100,105 Pharmacological inhibition of gastric acid secretion is required to avoid acid‐mediated enzyme inactivation when uncoated enzyme preparations are used. PERT preparations with evidence of efficacy are of porcine origin. A non‐porcine PERT formulation was developed but failed to meet its primary endpoint in a phase III clinical trial. 106 Patients on special diets, such as vegans or vegetarians, and those with religious reasons DOMINGUEZ‐MUÑOZ ET AL. - 9 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Comment: There is a debate about whether pancreatic injury causing PEI in AP is temporary or permanent. 179,180 A study of 370 patients at admission and 1795 at follow‐up reported a decrease in the prevalence of PEI from 62% at admission to 35% at 5 years, with the most significant decrease occurring in the first year. 40 This indicates that if PEI occurs, it may take several months or even years to resolve. To re‐evaluate the presence of PEI and potentially discontinue PERT, re‐testing for PEI at 3‐ month intervals after discharge is recommended. To rule out PEI resolution, it is recommended that those who remain on PERT be retested (e.g., at 6 and 12 months). 40 Is there any scenario in which empirical treatment for PEI can be started without diagnostic tests? Statement 5.6 Empirical treatment may be considered in the presence of symptoms of maldigestion or nutritional deficiencies, particularly after severe necrotizing pancreatitis. A clear response can be both diagnostic and therapeutic in PEI. Level of evidence:5;Percentage of agreement:95.3% Comment: Since the main goals of PEI therapy are to relieve gastrointestinal symptoms and improve the nutritional status of patients, empirical PERT may be considered in some patients after AP. 181 In cases with a high probability of PEI, such as patients with severe necrotizing pancreatitis, the negative predictive value of FE‐1 as a pancreatic function test for the diagnosis of PEI is not strong enough to avoid starting empirical PERT. What are the clinical consequences of PEI in patients with AP? Statement 5.7 The clinical consequences of PEI in patients with AP are comparable with those with other PEI etiologies (see Chapter 1). Level of evidence:1;Percentage of agreement:96.9% Is PEI associated with delayed recovery after AP? Statement 5.8 PEI may affect functional recovery, length of hospital stay, and the QoL during the early post‐AP period. Quality of evidence:moderate;Recommendation:weak (Grade 2B); Percentage of agreement:92.3% Comment: In a double‐blind randomized controlled trial of patients with abnormally low FE‐1 test results in the early phase of AP, those who received PERT tended to recover faster, with fewer days in the hospital, less weight loss, and an increase in the QoL compared with those who received placebo. 87 This study suggests the impact of PEI and its treatment during AP; however, stronger evidence is lacking. What is the treatment of PEI in patients after AP? Statement 5.9 PEI treatment after AP follows general recommendations (see Chapter 3). Level of evidence:1;Percentage of agreement:98.5% Should PERT be added to enteral nutrition in patients with AP? Statement 5.10 PERT can be added to enteral nutrition in patients with severely necrotizing AP; however, data on its efficacy and feasibility are scarce. Level of evidence:4;Percentage of agreement:93.5% Comment: For patients with PEI receiving enteral nutrition, PERT can be administered via a feeding tube that requires adjustments for gastric or jejunal delivery and is suitable for both continuous and bolus feeding methods. 27 Clinical improvements were observed when PERT was combined with enteral nutrition and used immediately. 112 Enzymes can be introduced into the feeding tube every 2 h or added directly to the formula. 27 What are the specific benefits of PERT in patients with AP? Statement 5.11 PERT is likely to relieve the symptoms of maldigestion and prevent nutritional deficiencies in patients with PEI after AP. However, specific data are lacking. There is insufficient evidence to support the use of PERT for PEI during admission for AP. Level of evidence:5;Percentage of agreement:93.8% Comment: In a study by Kahl et al., patients who underwent PERT tended to have better outcomes, but these improvements were not statistically significant. There was a positive trend in all QoL subscores associated with enzyme supplementation. 87 It should be noted that the sample size of this study was small, which limited the significance of the results. Similarly, Patankar et al. found no significant differences in laboratory or clinical outcomes, including total pain scores and analgesic requirements, between the groups. 182 The length of hospital stay was comparable between the placebo and PERT groups. 16 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License How should patients with PEI secondary to AP be monitored? Statement 5.12 In patients with PEI secondary to AP, and as a general recommendation, clinical symptoms, nutritional status, a non‐invasive test for PEI (e.g., FE‐1), and adherence to PERT can be monitored at 3, 6, and 12 months after hospital discharge, and then every 6–12 months in the case of persistent PEI. Level of evidence:5;Percentage of agreement:92.1% Comment: No prospective randomized trial has reported the benefit of individualized monitoring in patients with PEI after an episode of AP. As pancreatic function may recover in the first few months after AP, this assessment can be performed at the end of the acute episode and then at 3, 6, and 12 months. If the assessment shows thatexocrine pancreatic function hasreturned, further assessmentcan be stopped; however, if there is continuing evidence of PEI, monitoring should be continued at 6–12 months intervals. Monitoring includes clinical symptoms, FE‐1 concentrations, compliance with PERT, and nutritional status. Further detailed recommendations for nutritional assessment in PEI can be found in the recent ESPEN guidelines. 112 CHAPTER 6: PEI ASSOCIATED WITH PC What is the prevalence of PEI in patients with PC? Statement 6.1.1 PEI occurs in approximately 70% of patients with PC. It is more common in patients with tumors located in the pancreatic head and in those with advanced‐stage disease. Level of evidence:1;Percentage of agreement:100% Statement 6.1.2 The prevalence of PEI in patients with advanced PC increases with disease progression. Level of evidence:4;Percentage of agreement:98.4% Comment: According to a meta‐analysis, the pooled prevalence of PEI in advanced PC is 72% (95% CI: 55%–86%), 41 with significantly higher prevalence in tumors located in the pancreatic head (RR: 3.36, 95% CI: 1.07–10.54). 41 In a study using the 13C‐MTG breath test, the prevalence of PEI in patients with unresectable PC was 80%. 183 Finally, in a systematic review, the median preoperative prevalence of PEI was 44% before pancreatoduodenectomy, 20% before distal pancreatectomy, 63% before total pancreatectomy, and 25%–50% in patients with locally advanced PC. 59 A study of patients with a pancreatic head tumor showed that the prevalence of PEI at diagnosis was 66%, rising to 92% after a median follow‐up of 2 months. 184 What is the pathogenesis of PEI in patients with PC? Statement 6.2 PEI in PC is primarily caused by tumor obstruction of the main pancreatic duct. Atrophy, replacement of the pancreatic parenchyma, and loss of pancreatic exocrine tissue may also play roles. Level of evidence:1;Percentage of agreement:93.6% Comment: The main causes of PEI in patients with PC are obstruction of the main pancreatic duct with subsequent parenchymal atrophy proximal to the obstruction and loss of exocrine pancreatic tissue or its replacement by tumors and fibrotic tissue. 41,183,185–187 This obstruction impedes the flow of pancreatic enzymes and bicarbonates necessary for neutralizing gastric acid. 186 A double‐blind, prospective, randomized, single‐center interventional study concluded that pancreatic endoscopic drainage was associated with a significant improvement in exocrine pancreatic function in patients with unresectable PC, supporting the major role of ductal obstruction in the pathogenesis of PEI in patients with PC. 183 How can PEI be diagnosed in patients with PC? Statement 6.3 Diagnosis of PEI in patients with PC follows general recommendations (Chapter 2). Level of evidence:3;Percentage of agreement:96.9% What are the clinical consequences of PEI in patients with PC? Statement 6.4.1 PEI contributes to malnutrition and weight loss in patients with PC. Level of evidence:3;Percentage of agreement:100% Statement 6.4.2 PEI increases the risk of sarcopenia in patients with PC, which is associated with a poor prognosis. Level of evidence:3;Percentage of agreement:96.7% Statement 6.4.3 The severity of PEI based on the FE‐1 test is correlated with survival in patients with advanced PC. Level of evidence:3;Percentage of agreement:89.7% DOMINGUEZ‐MUÑOZ ET AL. - 17 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Statement 6.4.4 Untreated PEI affects the QoL in patients with PC. Level of evidence:4;Percentage of agreement:93.6% Comment: Weight loss in patients with PC is often caused by multiple factors, including PEI, which leads to potential nutritional deficiencies. The patients with PEI tend to have lower albumin levels. 188 A higher, although not statistically significant, prevalence of PEI has been reported in malnourished or at‐risk patients (42.7%) compared to their well‐nourished counterparts (26.7%) prior to pancreaticoduodenectomy. 189 In addition, a mouse model showed that the reduced exocrine pancreatic function associated with PC contributes to adipose tissue loss. 190 PEI is associated with sarcopenia in patients with pancreatic diseases, including cancer. 68 Sarcopenia, particularly during chemotherapy, is a predictor of poor survival in patients with PC. 191 Sarcopenia in patients undergoing surgery for PC is associated with a higher incidence of postoperative complications, higher 30‐day mortality rates, and reduced overall survival. 192 In the study by Partelli et al., FE‐1≤20 μg/g was an independent predictor of survival in patients with advanced PC. Median overall survival was significantly longer in patients with FE‐1>20 μg/g (11 months) than in those with FE‐1<20 μg/g (7 months). 188 The negative effect of PEI on QoL has been demonstrated using a structured questionnaire for patients with PC or their caregivers. 115 In this study, digestive symptoms and difficulties in managing diet were identified as significant problems. These factors negatively affect the QoL, increase feelings of social isolation, and contribute to caregiver distress. What is the treatment of PEI in patients with PC? Statement 6.5 Treatment of PEI in PC follows general recommendations (Chapter 3). Level of evidence:3;Percentage of agreement:93.8% What are the benefits of PERT in patients with PC? Statement 6.6.1 PERT improves PEI‐related symptoms in patients with PC. Level of evidence:3;Percentage of agreement:100% Statement 6.6.2 PERT can improve the nutritional status of patients with PC. Level of evidence:1;Percentage of agreement:98.4% Statement 6.6.3 PERT may positively affect overall survival in patients with PEI secondary to PC. Level of evidence:2;Percentage of agreement:91.8% Comment: In a pilot study, PERT significantly improved symptoms as measured by standardized QoL questionnaires. After 1 week of PERT, the calculated diarrhea scores, pancreatic pain, and liver pain improved significantly. After 3 weeks, there were significant improvements in pancreatic pain and bloating/gas symptoms. 193 In a retrospective analysis of patients with advanced PC receiving first‐line gemcitabine/nab‐paclitaxel, PERT significantly reduced floating or greasy/fatty stools at 3 months compared with controls. In addition, PERT doubled the number of patients who gained weight during the treatment. 194 In a randomized controlled trial of patients with inoperable pancreatic head cancer, PERT significantly helped maintain body weight, which was associated with a significantly higher total daily energy intake, whereas the placebo resulted in weight loss over 8 weeks. The CFA increased by 12% in the PERT group and decreased by 8% in the placebo group (50). However, two randomized controlled trials involving patients with unresectable PC found no benefit of PERT for >8 weeks on body weight, nutritional markers, subjective global assessment, or survival. 195 A meta‐analysis of three available randomized controlled trials showed only a trend toward a benefit for weight change with PERT. 196 Retrospective data support the survival benefits of PERT in patients with PC. 92,185 A meta‐analysis of prospective and retrospective observational studies showed a survival benefit of 3.8 months in patients treated with PERT as well as improvements in body weight and a trend toward better QoL. 41 How should patients with PEI secondary to PC be monitored? Statement 6.7 Patients with PC and PEI should be monitored regularly to ensure that they receive adequate management advice and that their symptoms are controlled. These patients should be reassessed regularly to ensure that they do not require enzyme dose escalation or nutritional support for anemia or other micronutrient deficiencies. Level of evidence:4;Percentage of agreement:95.1% Comment: After the initiation of PERT, patients with PEI should be reassessed to ensure an adequate response to therapy, as some patients may require enzyme dose escalation. Although scientific evidence is limited, many clinicians support individualized assessment. 27 A small qualitative study of patients who started PERT after pancreaticoduodenectomy reported persistent diarrhea and poor adherence to the PERT prescription information. 197 Further qualitative work with patients and their caregivers found that a lack of 18 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License information and advice on managing PEI was the most important unmet need and had a significant impact on the QoL. 115 CHAPTER 7: PEI IN CF AND CFTR‐RELATED DISORDERS (CFTR‐RD) What is the prevalence of PEI in CF and CFTR‐RD? Statement 7.1.1 PEI occurs in 75%–90% of patients with CF. Level of evidence:1;Percentage of agreement:96.49% Statement 7.1.2 The type of CFTR mutation determines the risk of PEI in patients with CF. Patients with severe biallelic (classes I, II, III, and VI) CFTR mutations develop PEI early in life. Level of evidence:1;Percentage of agreement:96.5% Statement 7.1.3 Patients with pancreatic sufficient (PS)‐CF who develop pancreatitis have an increased risk of developing PEI over time. Level of evidence:3;Percentage of agreement:96.5% Statement 7.1.4 PEI has a wide prevalence in patients with CFTR‐RD, with CP being the most common cause. Level of evidence:3;Percentage of agreement:96.5% Comment: Clinical studies have established an 80%–90% prevalence of PEI in patients with CF, 108,198,199 and only a small number maintain pancreatic function. In general, patients with CF develop PEI early in life, with the majority occurring before 1 year of age. 200 PEI is correlated with the genotype in patients with CF. 201,202 Individuals with two severe CFTR mutations (classes I, II, III, and VI) tend to develop PEI early, whereas those with two mild CFTR mutations (classes IV and V) or one severe and one mild mutation tend to develop PS at birth. 108,199,200,203,204 Alleles belonging to classes IV‐V are supposed to have some residual chloride channel activity at the epithelial apical membranes; thus, these patients maintain residual pancreatic function to be PS. However, cohort studies have shown that patients with PS‐CF with recurrent episodes of pancreatitis are at an increased risk (odds ratio[OR] 5.5) of developing PEI over time. 205 Patients with CFTR‐RD exhibit minimal pancreatic function, which leads to PS. Some patients develop pancreatitis, which evolves into PEI over time. 198,206,207 The prevalence of PEI in CP increases with disease duration, ranging 30%–90% of all etiologies confounded, 149,198,208 and 17–39% 209 in inherited forms of CP. Specific data for patients with CFTR‐RD are missing. What is the specific pathogenesis of PEI in patients with CF and CFTR‐RD? Statement 7.2.1 Exocrine pancreatic function in patients with CF is affected by duct obstruction and progressive damage, with consequent loss of functional pancreatic parenchyma. Level of evidence:2;Percentage of agreement:96.6% Statement 7.2.2 CFTR mutations are a significant contributor to PEI in patients with or without CF. Level of evidence:Level 1 (CF)—Level 4 (CFTR‐RD);Percentage of agreement:96.6% Comment: Reduced or nonexistent CFTR channel function results in reduced volume of pancreatic juice and hyperconcentration of macromolecules. This can lead to protein precipitation in the duct lumen causing obstruction, progressive pancreatic damage, and pancreatic atrophy. 204,210 Pancreatic diseases in patients with CF begin in utero and continue after birth. In CFTR‐RD, specific clinical featureslinkedtoCFTRdysfunctioninwhichCFhasbeenruledoutand carrying evidence of partially functioning CFTR protein, 211 PEI can appear due to reduced CFTR function or acute recurrent or CP. 212 How can PEI be diagnosed in patients with CF and those with CFTR‐RD? Statement 7.3 The diagnosis of PEI in patients with CF follows general recommendations (Chapter 2). Level of evidence:1;Percentage of agreement:98.3% As from when and how frequent should PEI be screened in patients with CF and CFTR‐RD? Statement 7.4.1 In patients with CF: The confirmation of PEI is required as soon as CF is diagnosed. A positive test result should be confirmed by a second test within 3 months. Patients with clearly established PEI do not need to undergo further PEI testing. Patients undergoing equivocal exocrine function tests should be monitored for PS. DOMINGUEZ‐MUÑOZ ET AL. - 19 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Level of evidence:4;Percentage of agreement:92.5% Children with pancreatic sufficiency should be monitored by annual FE‐1 or additionally in cases of failure to thrive, weight loss, abdominal pain, or diarrhea. Level of evidence:4;Percentage of agreement:92.5% In PS adults (≥16 years age), surveillance for development of PEI can be individualized according to genotype. �PS patients with a combination of two classes I‐III known to be associated with intermediate to high prevalence of PEI could be evaluated with the FE‐1 test annually and additionally if the development of PEI is suspected. �Patients with one or more class IV‐VI mutations, known to be associated with a low prevalence of PEI, could be evaluated upon suspected PEI development. Level of evidence:4;Percentage of agreement:92.5% Statement 7.4.2 In patients with CFTR‐RD: Evaluation of PEI is required as part of the workup for CFTR‐RD at any age. A positive test result should be confirmed by a second test within 3 months. Level of evidence:5;Percentage of agreement:92.5% PS patients with CFTR‐RD should be monitored by annual FE‐1 during infancy and childhood or additionally in cases of failure to thrive, weight loss, deficiencies in fat‐soluble vitamins, and episodes of AP or diarrhea. Level of evidence:4;Percentage of agreement:92.5% In PS adults (≥16 years age), surveillance for development of PEI can be individualized. �Clinical subtypes with evident recurrent episodes of AP or signs of CP development should be monitored annually using FE‐1. �Clinical subtypes with other clinical manifestations (congenital bilateral absence of the vas deferens or disseminated bronchiectasis) can be evaluated based on the suspected development of PEI. Level of evidence:5;Percentage of agreement:92.5% Comment: PEI is observed in the majority of patients with CF and develops with increasing prevalence during the first year of life. 213–217 Patients initially diagnosed with PS early in life have a high risk of declining exocrine function. 217–220 The loss of exocrine function has implications for the nutritional state and life expectancy of patients with CF. 47,213,214,221 The goal of nutritional treatment for patients with CF during early life is normal growth and prevention of nutritional deficiencies. The detection and treatment of exocrine failure in early life is important for achieving these goals. 215,222 For PS patients with CF and those with CFTR‐RD, the risk of developing PEI is more difficult to predict. Patients with signs of non‐CF‐specific pancreatic diseases such as recurrent AP or CP should be given extra attention during PEI surveillance testing. 199,223 Finally, monitoring for signs of exocrine failure (steatorrhea, weight loss, deficiencies in fat‐soluble vitamins, or distal intestinal obstruction syndrome) is recommended in the follow‐up of all PS patients with CF or CFTR‐ RD. 215,222 What are the clinical consequences of PEI in CF and CF‐related disorders? Statement 7.5 The clinical consequences of PEI in CF and CF‐related disorders are comparable to those of other etiologies (Chapter 1). Additionally, PEI and malnutrition in patients with CF negatively influence growth, pulmonary function, and survival. Level of evidence:1;Percentage of agreement:96.6% Comment: Historical studies convincingly highlight that a high‐ fat, high‐calorie diet and PERT promote the growth and survival of patients with CF (55). Further studies have confirmed the negative effects of poor nutritional status on pulmonary function and survival. 224,225 How should PERT be performed in patients with CF? Statement 7.6.1 PEI treatment in CF follows general recommendations (Chapter 3), with the particularity that the enzyme dose must be calculated according to age and body weight. Level of evidence:1;Percentage of agreement:96.2% Statement 7.6.2 Patients treated with PERT should be monitored for growth, nutritional status, and abdominal symptoms at regular intervals to determine the adequacy of treatment at every clinic visit for infants and every 3 months for older children, adolescents, and adults. Level of evidence:4;Percentage of agreement:96.2% Comment: In clinical practice, administration of enzyme pellets to infants can be difficult. If the infant refuses to take the enzyme pellets from a spoon with a little expressed breast milk or formula, the administration of an acidic puree, such as applesauce, may be successful. If the infant still refuses pellets, the use of unprotected powdered enzymes may need to be considered temporarily. Pancreatic enzymes should not be added to infant feed. For patients of all ages, powdered enzymes can be used to help digest enteral tube feedings, for example, when oral administration of enzymes is not possible or when jejunostomy feeds are required. 20 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Enzymes administered in this situation should not mix with the feed; they should be administered as bolus doses through enteral feeding tubes. When unprotected powdered enzymes are used, the addition of a PPI may help prevent the inactivation of lipase by gastric acid. For small children, enteric coated pancrelipase enzyme preparations have been shown to be safe, effective, and preferred by parents. Monitoring of growth and nutritional status at regular intervals to determine the adequacy of treatment is recommended at each monthly clinic visit for infants, every 3 months for children and adolescents, and every 6 months for adults. How should PERT be performed in patients with CFTR‐RD? Statement 7.7 PERT in patients with CFTR‐RD follows general recommendations (Chapter 3). Level of evidence:2;Percentage of agreement:98.2% How does potentiator/modulator therapy affect PEI in patients with CF and those with CFTR‐RD? Statement 7.8.1 Potentiators and modulators may improve exocrine pancreatic function when started early in patients with CFTR‐RD with eligible mutations. Level of evidence:3;Percentage of agreement:98.0% Statement 7.8.2 The current data are insufficient to amend the recommendations for PERT, nutritional requirements, and liposoluble vitamins in patients receiving potentiator/modulator therapy. Level of evidence:4;Percentage of agreement:98.0% Comment: Until the advent of modulation therapy, approximately 85% of patients with CF were reported to develop PEI by the age of 1 year. Recent clinical studies using the CFTR‐potentiator Ivacaftor (ARRIVAL, 226 KIWI, 227 and KLIMB 228 ) in children aged 1– 5 years support the improvement or recovery of exocrine pancreatic function. The ARRIVAL study, studying Ivacaftor in children aged 4 to <12 months 229 and 12 to <24 months 226 with ≥1 CFTR gating mutation, evidenced that levels of FE‐1 and immunoreactive trypsin (IRT) improved significantly between baseline and after 24 weeks of treatment. The KIWI 227 and follow‐up KLIMB 228 studies performed in children aged 2–5 years with a CFTR gating mutation showed similar significant improvements in exocrine pancreatic function. In children aged 2–5 years with homozygous F580del‐CFTR mutations treated with lumacaftor‐ivacaftor, significant improvements in exocrine pancreatic function (FE‐1 levels and IRT) were noted between baseline and 24 weeks of treatment. 230 Despite these encouraging results, the impact of modulators on PEI in older children is less clear, raising the question of a “window of opportunity” for reversing exocrine dysfunction. Thus, these data support the beneficial effects of modulators on exocrine pancreatic function, especially in young children with CF and those with milder mutations. Nevertheless, further studies are required to validate the data in larger patient cohorts. In addition, the impact of modulators/potentiators on the PERT dose has not yet been studied. In patients with PS‐CF and CFTR‐RD, a decline in exocrine function occurs later in life and may be accelerated by bouts of pancreatitis. Although data are limited, Ramsey et al. showed thatthe increased use of modulators (iva, iva þluma, or teza þiva) in patients with PS‐CF was correlated with a 65% relative reduction in hospitalizations for pancreatitis. 231 These data are further supported by case reports showing that modulators can prevent pancreatitis episodes in patients with PS‐CF and CFTR‐RD. 232–234 Although very promising, longer follow‐up is necessary to determine whether the use of modulators in patients with severe mutations (Class II) promotes the emergence of pancreatitis and secondary PEI development. In conclusion, our data suggest that modulators may restore exocrine function in (young) patients with PEI‐CF, preventing a further decline in pancreatic exocrine function in PS‐CF and pancreatitis episodes in patients with CFTR‐RD and PS‐CF. The impact of modulators on nutritional support, liposoluble vitamin supplementation, and PERT recommendations requires further investigation. CHAPTER 8: PEI AFTER PANCREATIC SURGERY What is the prevalence of PEI in patients after pancreatic surgery? Statement 8.1 The prevalence of PEI after pancreatic surgery is highly variable, ranging from 100% after total pancreatectomy to 10% in some reports after distal or central pancreatectomies. Level of evidence:1;Percentage of agreement:98.3% Comments: The prevalence of PEI after pancreatic surgery varies according to the surgical procedure, condition of the pancreas before surgery, tools used to diagnose PEI, and timing of pancreatic function assessment after surgery. The prevalence of PEI is 100% after total pancreatectomy, although more than half of patients do not develop PEI‐related symptoms. 42,235–237 According to a systematic review, the prevalence of PEI after pancreaticoduodenectomy is 92%. 59,236,238,239 After distal and central pancreatectomies, the prevalence of PEI is 10%–80%. 59,236,238,239 DOMINGUEZ‐MUÑOZ ET AL. - 21 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License What is the pathogenesis of PEI after pancreatic surgery? Statement 8.2 The pathogenesis of PEI after pancreatic surgery is multifactorial. The main contributing factors were the state of the pancreas before surgery, removal of the pancreatic parenchyma, disruption of the physiological postprandial stimulation of pancreatic secretion during duodenal resection, and inadequate mixing of pancreatic enzymes with nutrients after gastrointestinal reconstruction. Level of evidence:1;Percentage of agreement:98.4% Comments: The two main factors contributing to the development of PEI after pancreaticoduodenectomy are duodenal removal and loss of pancreatic parenchyma. The former leads to the disruption of autonomic control and inadequate activation of pancreatic digestive enzymes. The latter leads to an overall reduction in pancreatic exocrine secretion. 240–242 PEI after distal pancreatectomy and central pancreatectomy depends on the volume of the remnant pancreas, 243–247 with a remnant pancreatic volume <39.5% predictive of PEI. 247 In addition, direct inactivation of pancreatic enzymes by gastric acid may be a contributing factor when pancreatogastrostomy is performed after pancreaticoduodenectomy or central pancreatectomy. 248,249 How should PEI be diagnosed in patients after pancreatic surgery? Statement 8.3 The diagnosis of PEI in patients after pancreatic surgery mainly follows the general rules described in Chapter 2 with two exceptions. First, no diagnostic confirmation is required after total pancreatectomy, and second, the FE‐1 test is not suitable for the diagnosis of PEI after pancreaticoduodenectomy. Level of evidence:1;Percentage of agreement:84.2% Comment: The anatomical and functional consequences of pancreaticoduodenectomy render the FE‐1 test and the proposed cut‐off values inadequate for the diagnosis of PEI. Therefore, a universally accepted approach for diagnosing PEI after pancreatic surgery is lacking. The most appropriate diagnostic test seems to be the calculation of CFA. 250,251 Another available but not fully validated diagnostic test is the 13C‐MTG breath test. 24 What are the clinical consequences of PEI after pancreatic surgery? Statement 8.4 The clinical consequences of PEI after pancreatic surgery are similar to those of other clinical conditions (see Chapter 1). Level of evidence:2;Percentage of agreement:98.4% What is specific for the treatment of PEI in patients after pancreatic surgery? Statement 8.5 PEI treatment after pancreatic surgery follows the general rules described in Chapter 3. However, the initial oral dose of pancreatic enzymes required in patients after total pancreatectomy and pancreaticoduodenectomy may be higher than that generally recommended for patients with PEI secondary to other conditions. Level of evidence:4;Percentage of agreement:91.7% What are the benefits of PERT after pancreatic surgery? Statement 8.6 The benefits of PERT in patients with PEI after pancreatic surgery are similar to those in patients with other clinical conditions (see Chapter 3). Level of evidence:2;Percentage of agreement:98.4% How should patients with PEI after pancreatic surgery be monitored? Statement 8.7 Recommendations for the monitoring and follow‐up of patients with PEI after pancreatic surgery follow the general rules described in Chapter 3. Level of evidence:5;Percentage of agreement:98.3% Comment: Particularly, after pancreatic surgery, other causes of abdominal symptoms should be investigated if the clinical response to PERT is inadequate. The differential diagnoses of PEI after surgery include superior mesenteric artery revascularization, dissection‐ associated diarrhea syndrome, small intestinal bacterial overgrowth, and dumping syndrome. Similar to other causes of PEI, oncological metabolic factors leading to malnutrition, bile acid malabsorption, infectious diarrhea (e.g., Clostridium difficile), lactase deficiency, food intolerance, CeD, IBD, IBS, and diabetic diarrhea should be considered in patients with an inadequate clinical response to PERT. CHAPTER 9: PEI AFTER UPPER GASTROINTESTINAL (ESOPHAGEAL, GASTRIC, AND BARIATRIC) SURGERIES What is the prevalence of PEI in patients who have undergone upper GI surgery? Statement 9.1 The prevalence of PEI after upper gastrointestinal surgery is 9%–67%, depending on the type of surgery and the test used to diagnose PEI. 22 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Level of evidence:3;Percentage of agreement:96.9% Comment: Three prospective cohort studies measured exocrine pancreatic function after esophagectomy and found PEI in 16%–57% of patients. 252–255 Clinical data on the prevalence of PEI after gastric surgery are limited to small studies. 256–258 A study using pancreatic stimulation with intravenous secretin and cerulein showed that patients after gastric surgery had lower bicarbonate and lipase secretions and 67% had steatorrhea. 258 After total gastrectomy for gastric cancer, all patients develop severe PEI, as measured by the secretin‐cerulein test, within 3 months of surgery. 256 Subtotal gastrectomy leads to altered fat digestion and absorption in about two‐thirds of patients, particularly after Roux‐ en‐Y reconstruction compared with Billroth I reconstruction. 257 Based on a small number of studies, the prevalence of PEI after bariatric surgery is 9%–48%. 259–261 In a study using FE‐1, 48% of the patients after distal Roux‐en‐Y gastric bypass (RYGB) and 19% after proximal RYGB showed reduced pancreatic secretion. 259 In another study, low pancreatic secretions were found in 10.3% and 4.2% of the patients after RYGB and gastric sleeve, respectively. 260 Using the 13C‐MTG breath test, the prevalence of PEI in patients after bariatric surgery ranges from 4.3% after general surgery and 8.3% after RYGB to 75% after biliopancreatic diversion with duodenal switch (22). What is the specific pathogenesis of PEI in patients who undergo upper gastrointestinal surgery? Statement 9.2 PEI after upper gastrointestinal surgery may be the result of impaired stimulation of digestive enzyme secretion (humoral and neural) and postprandial gastrointestinal asynchrony. Level of evidence:5;Percentage of agreement:98.4% Comment: Upper gastrointestinal surgery results in physiological changes that contribute to the development of PEI due to impaired postprandial stimulation of pancreatic secretion and asynchrony between the gastric emptying of nutrients and biliopancreatic secretion. 43 Therefore, the accuracy of quantifying pancreatic secretion using FE‐1 testing for the diagnosis of PEI in these conditions was lower than that in patients with normal gastrointestinal anatomy. How can PEI be diagnosed in patients who underwent upper gastrointestinal surgery? Statement 9.3.1 FE‐1 is not a reliable test for PEI after upper gastrointestinal surgery. Level of evidence:5;Percentage of agreement:83.6% Statement 9.3.2 Although not specific to PEI, symptoms of maldigestion and nutritional deficiencies can be used to suspect PEI in patients who have undergone upper gastrointestinal surgery. Level of evidence:5;Percentage of agreement:84.6% Statement 9.3.3 The 13C‐MTG breath test and quantification of the CFA could be used to diagnose PEI after upper gastrointestinal surgery. Level of evidence:5;Percentage of agreement:91.8% Comment: PEI after upper gastrointestinal surgery cannot be diagnosed using the same methodology as that in patients with normal gastrointestinal anatomy (see Chapter 2). FE‐1 allows the assessment of pancreatic secretion but does not measure the effectof postprandial asynchrony between gastric emptying of chyme and pancreatic secretion during food digestion. In contrast to FE‐1, the 13C‐MTG breath test and fecal fat quantification assess the digestion and absorption of fat, and can therefore be used to diagnose PEI after upper GI surgery. 43 What are the clinical consequences of PEI in patients who undergo upper gastrointestinal surgery? Statement 9.4 The clinical consequences of PEI in patients after upper gastrointestinal surgery may be similar to those of other causes PEI (see Chapter 1). Level of evidence:3;Percentage of agreement:93.9% What is the treatment of PEI in patients who undergo upper gastrointestinal surgery? Statement 9.5 PEI treatment after upper gastrointestinal surgery follows general recommendations (see Chapter 3). Level of evidence:5;Percentage of agreement:96.9% Comment: There is little evidence on whether PERT capsules should be opened and the pellets swallowed with acidic liquid or semi‐solid food (pH <5.5) after gastrectomy to allow their better mixing with food. 262 PERT has been suggested to prevent postoperative maldigestion and weight loss. 256 After bariatric surgery, appropriate PERT should be considered part of the management algorithm for patients with confirmed PEI and symptoms or nutritional deficiencies suggestive of this complication. 263 However, the role of PERT in these patients is unclear because there is insufficient DOMINGUEZ‐MUÑOZ ET AL. - 23 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License evidence to determine whether or to what extent, this therapy interferes with the goals of bariatric surgery. 259 CHAPTER 10: PEI AND DIABETES MELLITUS (DM) What is the prevalence of PEI in patients with DM? Statement 10.1 Reduced pancreatic secretion, as assessed by FE‐1 levels, is common in patients with type 1 and type 2 DM. The prevalence of PEI, according to the agreed‐upon definition (Chapter 1) is unknown. Level of evidence:3;Percentage of agreement:94.2% Comment: Reduced pancreatic secretion, defined by low FE‐1, is consistently more common in people with DM than in controls, with a prevalence of 10%–50%. 264,265 A meta‐analysis reported a pooled prevalence of 22% (95% CI: 15%–31%) in type 2 DM. 266 These figures may be overestimated because studies that strictly excluded pancreatogenic diabetes reported a prevalence of 5.4%. 267 Reduced pancreatic secretion, as defined by low FE‐ 1, appears more common in type 1 DM than in type 2 DM and may correlate with DM duration, 268–270 but this is still debated. What is the pathogenesis of PEI in patients with DM? Statement 10.2 The pathogenesis of PEI in patients with DM is multifactorial, complex, and incompletely understood. Level of evidence:4;Percentage of agreement:97.1% Comment: The proposed mechanisms of PEI in patients with DM include the loss of the trophic and stimulatory effects of insulin on the exocrine pancreas, 271 pancreatic atrophy, autonomic dysfunction, 271,272 fibrosis, pancreatic steatosis, and dysregulation of other islet hormones such as glucagon and somatostatin. 271 How can PEI be diagnosed in patients with DM? Statement 10.3 The diagnosis of PEI in patients with DM follows general recommendations (Chapter 2). Level of evidence:1;Percentage of agreement:100% Comment: PEI symptoms are usually mild in patients with DM. Typical abdominal discomfort, diarrhea, and flatulence may be misinterpreted as drug‐related (metformin and glucagon‐like peptide‐1 agonists) or secondary to diabetic neuropathy. Studies showing weak correlations between fecal fat excretion, pancreatic function tests, and FE‐1 levels in individuals with DM emphasize the need to consider alternative causes of steatorrhea such as CeD and bacterial overgrowth in the small intestine. 268 Should patients with DM be screened for PEI? Statement 10.4 Patients with types 1 and 2 DM should only be screened for symptoms or nutritional deficiencies consistent with PEI. Level of evidence:3;Percentage of agreement:94.2% Comment: Although reduced pancreatic secretions may be common in patients with DM, general screening is not recommended. However, symptoms consistent with PEI should be carefully assessed. If type 3c (pancreatogenic) DM is suspected, exocrine pancreatic function should be assessed. What are the specific clinical consequences of PEI in patients with DM? Statement 10.5 The clinical consequences of PEI in patients with DM are similar to those in other clinical conditions (Chapter 1). The development of PEI in patients with DM should raise awareness of possible underlying pancreatic diseases to ensure early diagnosis and treatment. Level of evidence:5;Percentage of agreement:98.6% Comment: Both pancreatitis and pancreatic malignancies are associated with PEI. As patients with DM are at an increased risk of both conditions, the development of PEI may require further investigation in suspected cases. What is the specific treatment of PEI in patients with DM? Statement 10.6 PEI treatment in patients with DM patients follows general recommendations (Chapter 3). Level of evidence:5;Percentage of agreement:97.2% What are the specific benefits of PERT in patients with DM? Statement 10.7 In addition to the general benefits of PERT mentioned in Chapter 3, glucose homeostasis may also be positively influenced by PERT; 24 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License however, the evidence is conflicting. Treatment with PEI may improve cardiovascular risk in patients with DM. Level of evidence:5;Percentage of agreement:86.2% Comment: PEI is associated with an increased cardiovascular risk. 273 Therefore, its treatment may be particularly beneficial for patients with DM who are at a high risk of cardiovascular disease. How should patients with DM and PEI be monitored? Statement 10.8 Monitoring of patients with DM and PEI follows general recommendations (Chapter 3). Level of evidence:3;Percentage of agreement:98.6% Comment: Special attention should be paid to the diagnosis and treatment of osteoporosis as it is a common complication of both conditions. 72,274 What is the relation between PEI and type 3c (pancreatogenic) DM? Statement 10.9 Both PEI and type 3c DM result from the same pancreatic injury, most commonly CP, PC, or previous pancreatic surgery, and less commonly from AP, CF, or hemochromatosis. Level of evidence:5;Percentage of agreement:97.0% Comment: Surgical resection of the pancreas is perhaps the most obvious cause of type 3c DM, but it accounts for only 2% of cases. 275 CHAPTER 11: PEI IN OTHER CONDITIONS What is the prevalence and clinical relevance of PEI in aging? Statement 11.1 Exocrine pancreatic function may be impaired with aging. Low FE‐1 levels have been reported in 21.7% of patients aged >60 years and 11.5% of people aged 50–75 years. Level of evidence:4;Percentage of agreement:93.9% Comment: Aging is associated with changes in the pancreatic volume, structure, and perfusion. 276 Although studies on exocrine pancreatic function in older patients do not unanimously favor old age as a risk factor for PEI, 277–279 other reports support this claim. 280–288 In the old age, significantly lower enzyme and/or bicarbonate output following the secretin test has been reported 281–285 and confirmed using FE‐1 as an indicator of exocrine secretion. 287,288 The largest study conducted so far in a population‐based cohort of 914 participants aged 50–75 years showed low FE‐1 levels (<200 μg/g) in 11.5% of the study participants. 287 In another study of 159 patients, low FE‐1 levels were reported in 21.7% of participants aged >60 years. 288 Although the clinical relevance of PEI in aging is unknown, older individuals with proven PEI should not be treated differently from other patients with this condition. What is the prevalence and clinical relevance of PEI in non‐alcoholic fatty pancreas disease? Statement 11.2 The clinical relevance of fatty pancreas and whether it can cause PEI remain unclear. Level of evidence:4;Percentage of agreement:95.3% Comment: A systematic review of five studies on fatty pancreas showed PEI in 9%–56% of patients. 289 Among 31 patients with MRI signs of pancreatic steatosis and 25 controls, FE‐1 levels were lower in the fatty pancreas group. 290 Another study that used the N‐benzoyl‐L‐ tyrosyl‐p‐amino benzoic acid (BT‐PABA) pancreatic function test did not find any association between the amount of pancreatic fat on CT and PEI. 291 In contrast, an inverse relationship between the amount of pancreaticfattyaccumulation on MRIand FE‐1levelswas reportedina large population‐based study. 292 Fatty pancreas is particularly common in patients with non‐alcoholic fatty liver disease; one out of each of the four patients has a low FE‐1, but the 13C‐MTG‐breath test is normal, and symptoms of PEI and nutritional deficiencies are lacking. 289 What is the prevalence and clinical relevance of PEI in hemochromatosis? Statement 11.3 The prevalence and clinical relevance of PEI in hemochromatosis is not known. Level of evidence:5;Percentage of agreement:98.4% Comment: Data on the association between hemochromatosis and PEI are lacking. Two small studies were published decades ago 293,294 and a few case reports were published thereafter. 295,296 All other available data came from studies performed on patients with other iron overload disorders such as beta‐thalassemia major. 297–299 The studies were heterogeneous and used different methods to diagnose PEI, making the results difficult to interpret. What is the prevalence and clinical relevance of PEI in celiac disease? Statement 11.4 Low FE‐1 levels and pathological BT‐PABA test have been reported in 10.5%–46.5% of new patients with CeD (pooled prevalence 26.2%). 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DOMINGUEZ‐MUÑOZ ET AL. - 41 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Emma Martinez‐Moneo—has received honoraria from Viatris Julia Mayerle—has received research grants from DFG, BMBF, DKH, and honoraria from the Falk Foundation Johanna Ockenga—has received a research grant from the Innovationsfond, GBA (German government) Alexey Okhlobystin—has received honoraria from Abbott Laboratories Salvatore Paiella—has received honoraria from AlphaTau Medical Lukas Perkhofer—has received research grants from Deutsche Forschungsgesellschaft, German Cancer Aid, and honoraria from AstraZeneca, Servier, and Roche Mary Phillips—has recieved honoraria from Viatris and Nutricia Clinical Care Goran Poropat—has received honoraria from Abbott Nutrition, Fresenius, Sandoz, and Krka Farma Vinciane Rebours—has received research grants and honoraria from Mayoly Spindler and Viatris Jonas Rosendahl—has received honoraria from the Falk Foundation, Nordmark, Viatris, Alexxion, MicroTech Oleg Shvets—has received honoraria from Abbott, Takeda, Berlin‐Chemie, Nutricia, B.Braun Hester Timmerhuis—has received honoraria from Viatris and Tramedico Miroslav Vujasinovic—has received honoraria from Viatris and Abbott Michael Wilschanski—has received a research grant from Vertex Pharmaceuticals, and honoraria from Synspira 48 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Servicio Galego De Saude, Wiley Online Library on [10/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License