Received: 23 May 2024

DOI: 10.1002/ueg2.12674

GUIDELINE
- Accepted: 12 August 2024

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‐Muñoz1 | Miroslav Vujasinovic2 | Daniel de la Iglesia3 |

Djuna Cahen4 | Gabriele Capurso5 | Natalya Gubergrits6 | Peter Hegyi7,8,9,10 |
Pali Hungin11 | Johann Ockenga12 | Salvatore Paiella13 | Lukas Perkhofer14 |
Vinciane Rebours15 | Jonas Rosendahl16 | Roberto Salvia13 | Isabelle Scheers17 |
Andrea Szentesi8 | Stefanos Bonovas18,19 | Daniele Piovani18,19 |
J. Matthias Löhr20 | 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

-
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Correspondence
J. Enrique Dominguez‐Muñoz, Department of Abstract
Gastroenterology and Hepatology, University Pancreatic exocrine insufficiency (PEI) is defined as a reduction in pancreatic
Hospital of Santiago de Compostela,
Choupanna s/n, Santiago de Compostela exocrine secretion below the level that allows the normal digestion of nutrients.
15706, Spain. Pancreatic disease and surgery are the main causes of PEI. However, other con-
Email: [email protected]
ditions and upper gastrointestinal surgery can also affect the digestive function of
Funding information the pancreas. PEI can cause symptoms of nutritional malabsorption
United European Gastroenterology, Grant/
and deficiencies, which affect the quality of life and increase morbidity and mor-
Award Number: Grant number unknown
tality. These guidelines were developed following the United European Gastro-
enterology 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. State-
ments 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 sec-
ondary to pancreatic disease, pancreatic surgery, or other metabolic or gastro-
enterological 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 diseases,29 although the number of relevant publications is

increasing.30
Pancreatic exocrine insufficiency (PEI) has long been thought to be the Two interrelated issues have emerged about PEI. Pancreatic
result of a secretory deficiency of enzymes and/or bicarbonates from exocrine insufficiency must be considered a maldigestion syndrome
the pancreas.1 As a result, PEI has been observed almost exclusively in rather than an isolated organ defect. As a consequence, the diagnosis
the context of pancreatic diseases, primarily chronic pancreatitis (CP) and treatment of PEI must go beyond the pancreas and require a
and cystic fibrosis (CF) and later in pancreatic cancer (PC) or after more holistic view, which has led to a new definition of PEI (Chapter
resective pancreatic surgery. Accordingly, guidelines addressing PEI 1). In this guideline, we have reviewed many other conditions of PEI,
have focused almost exclusively on these four conditions. The first some of which have anatomically intact pancreas but impaired
evidence‐based guidelines using the Oxford or Grading of Recom- intraluminal pancreatic enzyme activity. For “normal” digestion, food
mendations, Assessment, Development, and Evaluation (GRADE) sys- and pancreatic enzymes must meet at the right time, place, and
tems to address PEI in the context of CP were published in 20122 environment.31
(Figure 1). Following an award from the United European Gastroen- In addition to the need for a revised definition of PEI and increased
terology (UEG),28 the first European guidelines were developed and awareness of this condition in some pancreatic and extrapancreatic
published in 2017.24 It has recently been noted that there is a paucity of diseases, the considerable variability in diagnostic and therapeutic
research on PEI in the general population and in patients with non‐ approaches to PEI in different clinical scenarios and centers across
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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F I G U R E 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;
Australia6–8; Belgium9; Canada10; Cochrane11; German Society for Digestive and Metabolic Diseases (DGVS)12; Hungary13; Italy14,15; Japan
Pancreas Society (JPS)16; Poland17; Russia18,19; Spain20,21; South Africa22; Turkey23; United European Gastroenterology (UEG)24; Romania25;
Sweden 26; United Kingdom.27 CP, chronic pancreatitis; PEI, pancreatic exocrine insufficiency.

FIGURE 2 Unmet needs, lacking scientific evidence, and future directions.

Europe and non‐European countries has been identified as an unmet METHODS

need that justifies the development of this guideline.
We also found a lack of high‐quality prospective clinical trials in The UEG framework for the development of high‐quality clinical
many areas of PEI (Figure 2). These new UEG guidelines are therefore guidelines, as proposed by the UEG Quality of Care Taskforce, was
unique but can only be seen as the first attempt in this direction. adhered to throughout the guideline's development.32
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
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TABLE 1 Overview of the working groups.

Scope and purpose
1. Concept, pathogenesis, and clinical relevance

In addition to defining the general concept, mechanisms, and conse- 2. A general diagnostic approach to PEI
quences of PEI, this guideline aims to provide evidence‐based rec- 3. A general therapeutic approach to PEI
ommendations for the general diagnosis and treatment of PEI in
4. PEI secondary to CP
clinical practice. It also addresses the specificity of PEI under various
5. PEI after acute pancreatitis (AP)
pancreatic and extrapancreatic diseases and conditions. The primary
health objectives of this guideline include accurate diagnosis, optimal 6. PEI associated with PC

treatment strategies, and prevention of complications. By following 7. PEI secondary to CF

these guidelines, healthcare professionals will be able to better in- 8. PEI after pancreatic surgery
crease the quality of life (QoL), minimize symptoms, and improve
9. PEI after esophageal, gastric, and bariatric surgery
overall outcomes in their patients.
10. PEI in patients with type 1 and type 2 diabetes

11. PEI in other conditions

Steering Committee and supporting societies Abbreviations: CF, cystic fibrosis; CP, chronic pancreatitis; PC,
pancreatic cancer; PEI, pancreatic exocrine insufficiency.
Members of the Steering Committee were selected based on their
expertise in the field, ability to contribute to the work process, and The first meeting of the group was held during the UEG Week in
32
personal experience as effective team members. They were familiar Vienna, Austria (October 2022). The WGs were finalized, and a
with the methodology of several previous guidelines12,24,33 and their leader responsible for each group was appointed (Table 1).
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 pro- Definition of search questions (PICO)
tocol and the UEG application. The Steering Group consulted experts in
methodology and research synthesis who were actively involved in all Following the meeting in Vienna, the WGs commenced the formula-
stages of the process. tion of the questions in accordance with the recommendations set
The EPC invited other UEG Specialist Member Societies to join forth by the Steering Committee (Appendix 1). These questions were
this project with the aim of developing transversal multidisciplinary subsequently endorsed by the entire group. In order to incorporate the
guidelines to be adopted by all specialties in Europe. The following patient perspective, questions were shared with patient associations.
societies confirmed their participation: the European Digestive The PC Europe (PCE), the Swedish patient organization PALEMA, and
Surgery (EDS), European Society for Pediatric Gastroenterology, the German “Arbeitskreis der Pankreatektomierten” (AdP) were
Hepatology and Nutrition (ESPGHAN), European Society for Clinical engaged as organizations representing patients to provide their
Nutrition and Metabolism (ESPEN), European Society of Digestive feedback on the drafted PICO questions (see acknowledgments
Oncology (ESDO), and European Society of Primary Care Gastro- section).
enterology (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 Search for scientific evidence
guidelines.
A comprehensive search for scientific evidence was performed across
the MEDLINE, Embase, Scopus, and Cochrane Central Register of
Working groups Controlled Trial databases. The search strategy used for each chapter
is outlined in Appendix 1. A stepwise approach was used to include
The Steering Committee, in collaboration with the other participating studies as follows: systematic reviews and meta‐analyses, randomized
societies, designated Working Group (WG) representatives for the controlled clinical trials, case‐control studies, observational cross‐
different topics within the guideline's scope and invited experts from a sectional and longitudinal cohort studies, and other types of evi-
range of medical specialties to contribute to them. Conflict of interest dence. The following studies were considered eligible for inclusion:
(COI) forms were distributed to all participants, and signed scanned studies of PEI associated with any pancreatic or extrapancreatic dis-
copies were sent to the UEG headquarters in Vienna in accordance ease or condition, including patients of any age, conducted in any
with the UEG rules. A request was made to all of the participants for country, and published in full text in English in peer‐reviewed journals.
updated COIs to be provided at 6‐month intervals over the duration of The following studies were excluded: narrative reviews, editorials,
the working process. abstracts or letters; those published in non‐peer‐reviewed journals; in
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DOMINGUEZ‐MUÑOZ ET AL.
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vitro and animal experimental studies; and studies published in lan- CHAPTER 1: CONCEPT, PATHOGENESIS, AND
guages other than English. CLINICAL RELEVANCE OF PEI

What is the definition of PEI?

Grade quality of evidence, and definition of
statements and comments Statement 1.1

In light of the available evidence, statements were formulated in order PEI is defined as a reduction in the exocrine pancreatic secretion
to address these questions. The statement format included the ques- and/or intraluminal activity of pancreatic enzymes below the level
tion, statement and level of evidence. The statements were followed by that allows normal digestion of nutrients. PEI is associated with the
qualifying comments written by each WG and reviewed by the Steering malabsorption of nutrients and may result in intestinal symptoms
Committee. Relevant comments and suggestions from the global and/or nutritional deficiencies.
consensus group were also considered. Statements were formulated in Consensus; Percentage of agreement: 97.4%
the context of population/problem, intervention, comparison, and Comment: Failure of the exocrine pancreas to deliver the
35
outcome (PICO) questions where applicable (see Appendix 1). The required levels of enzymes to the intestinal lumen for normal
quality of evidence was appraised according to the Oxford Center for nutrient digestion is the main factor defining PEI.24,27,38 However,
32,36 37
Evidence‐Based Medicine system and the GRADE system. The the clinical manifestation of PEI is variably influenced by other
WGs were supported by two expert methodologists throughout the relevant factors; therefore, the threshold for the clinical manifesta-
process of searching, selecting, and evaluating the scientific evidence tion of PEI varies among patients. The concept of PEI implies that
as well as writing the statements. The methodologists also provided pancreatic enzyme replacement therapy (PERT) can restore the
training in basic guideline methodology, advised during the develop- digestion and absorption of nutrients.
ment process, and reviewed the draft guideline manuscript.

What are the mechanisms leading to PEI?

Consensus process
Statement 1.2
All questions, statements, and related comments were uploaded to a
designated platform and subjected to a repeated Delphi process for all The mechanisms leading to PEI primarily include the reduced
of the participants in the Guideline Consortium. It was requested that secretion of pancreatic enzymes and bicarbonates due to pancreatic
members of the WGs provide updates on any potential conflicts of disease or insufficient postprandial stimulation of the exocrine
interest on a regular basis (see Appendix 2). In the event of a clear COI, pancreas.
members were obliged to abstain from voting on the specific topic in Level of evidence: 1; Percentage of agreement: 97.6%
question. A secretary provided comprehensive assistance throughout Comment: Decreased pancreatic enzyme secretion is the primary
the entirety of the working process. mechanism of PEI. Common causes of decreased secretion include loss
A level of agreement of 80% or higher was deemed to be indicative of functional exocrine pancreatic tissue, such as in CP, CF, necrotizing
of consensus. Statements with less than 80% agreement were returned pancreatitis, or pancreatic resection, and pancreatic ductal obstruc-
to the WG for further consideration. Updated versions were discussed tion, such as in PC.39–42 Reduced postprandial vagal (autonomic nerve
at the EPC meeting in Alpbach, Austria (June 2023), including a round division) and hormonal (low cholecystokinin [CCK] and secretin
of Test and Evaluation Directorate (TED) voting in accordance with the release) stimulation of pancreatic secretion is an additional factor that
previously described methodology, until an agreement was leads to PEI in patients after pancreaticoduodenectomy, gastrectomy,
reached.24,33 The degree of consensus was indicated alongside the or gastric bypass.43–46
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 manu- What is the impact of factors other than pancreatic
script was prepared and distributed to the WG coordinators and secretion on PEI?
methodologists for their comments. The resulting guidelines were then
collated and sent to independent non‐European expert pancreatolo- Statement 1.3
gists representing the Japanese Pancreas Society, the Korean Bil-
iopancreatic Association, and the Latin American Pancreatic Study Factors other than pancreatic secretion, mainly gastrointestinal
Group for review and comments (see Acknowledgments). A final round anatomy and intraluminal pH, also play important roles in the clinical
of adjustments was then made. The key concepts and recommenda- manifestations of PEI.
tions of the guidelines are highlighted in Figure 3. Level of evidence: 3; Percentage of agreement: 97.6%
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F I G U R E 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 Level of evidence: 1; Percentage of agreement: 97.6%
several factors, including gastrointestinal anatomy, intraluminal pH, Comment: Intestinal symptoms associated with PEI include diar-
compensatory activity of non‐pancreatic digestive enzymes, bowel rhea, steatorrhea, bloating, abdominal cramps, and flatulence.47
38,43,44
function, dietary habits, and nutritional requirements. In Nutritional deficiencies typically include protein, fat‐soluble vitamins,
addition to the altered vagal and hormonal postprandial stimulation and other micronutrient deficiencies associated with weight loss,
of pancreatic secretion, changes in the upper gastrointestinal tract osteoporosis, and sarcopenia.47–49 Patients with PEI are also prone to
due to surgery may affect intraluminal protease activation (low small intestinal bacterial overgrowth and other significant dysbioses of
intestinal endopeptidase secretion) and the mixing of pancreatic the gut microbiome.50–52 Due to various factors that may influence the
enzymes with chyme. The digestive activity of secreted pancreatic threshold and type of clinical manifestations of PEI, there is high vari-
enzymes depends on the intraluminal pH, and pancreatic enzymes ability in the symptoms and nutritional consequences of PEI among
are inactivated at pH values below 4. Salivary amylase, gastric patients.47 Therefore, PEI has a variable impact on the QoL and long‐
pepsin and lipase, and intestinal disaccharidases and peptidases term complications in different patients.
partially compensate for pancreatic maldigestion. Bowel function,
dietary habits, and nutritional requirements may influence the
development of symptoms and nutritional deficiencies. CHAPTER 2: A GENERAL DIAGNOSTIC APPROACH
TO PEI
What are the consequences and clinical relevance
of PEI? When is a diagnostic work‐up for the detection of PEI
indicated?
Statement 1.4
Statement 2.1
Regardless of the cause of PEI, intestinal symptoms and nutritional
deficiencies are the main clinical manifestations and consequences of Diagnostic work‐up for PEI is indicated in the presence of pre‐existing
PEI, which can affect the QoL and increase the risk of long‐term high‐risk conditions such as CF, CP, acute necrotizing pancreatitis, PC,
malnutrition‐related complications. or previous pancreatic surgery. PEI may also be considered in the
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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differential diagnosis of patients with symptoms suggestive of mal- Comments: The symptoms commonly associated with PEI include
digestion and malabsorption, such as steatorrhea or chronic diarrhea. steatorrhea, voluminous and foul‐smelling stools, diarrhea, flatulence,
Level of evidence: 3; Percentage of agreement: 97.0% bloating, abdominal discomfort, and weight loss. In clinical studies on
Comment: Several pancreatic conditions warrant a diagnostic patients with confirmed PEI secondary to different pancreatic dis-
work‐up to identify PEI due to a high pre‐test probability.8,27,53–55 eases, the frequency of clinically evident steatorrhea ranged 15%–
Additionally, the diagnosis of PEI should be considered in the dif- 70%, and the frequency of flatulence ranged 55%–100%.47 PEI can be
ferential diagnosis of steatorrhea or chronic diarrhea, suggesting diagnosed if clinically evident steatorrhea is present in patients with
maldigestion and malabsorption of nutrients.56 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
How can PEI be diagnosed? support the diagnosis of PEI. Diagnosis of PEI in patients with an un-
diagnosed pancreatic disease or history of pancreatic surgery can be
Statement 2.2.1 challenging because of the nonspecific nature of PEI symptoms.

In general, the diagnosis of PEI should be based on a combined

assessment of symptoms, nutritional status, and pancreatic function What is the role of nutritional assessment in the
in an appropriate clinical context. diagnosis of PEI, and what methods can be used to
Level of evidence: 3; Percentage of agreement: 97.3% assess the nutritional status of these patients?

Statement 2.4.1
Statement 2.2.2
Patients with PEI often have nutritional deficiencies, and nutritional
Confirmation of PEI may not always require pancreatic function tests assessment can aid in the diagnosis of PEI in patients with pancreatic
in patients with a high likelihood of PEI, such as those with pancreatic disease or a history of pancreatic surgery.
head cancer or those who have undergone pancreaticoduodenectomy Level of evidence: 3; Percentage of agreement: 97.0%
or total pancreatectomy.
Level of evidence: 2; Percentage of agreement: 97.3%
Comments: Due to their limited specificity, PEI cannot be diag- Statement 2.4.2
nosed solely based on commonly available pancreatic function
tests.57,58 Symptoms and nutritional deficiencies are not specific to The nutritional status of patients with PEI is evaluated primarily
PEI.47 Therefore, a combined assessment of the symptoms, nutri- using anthropometric parameters. If malnutrition is suspected, blood
tional status, and pancreatic function in each pertinent clinical parameters of malnutrition should be assessed.
context may be appropriate for diagnosing PEI in clinical practice. Level of evidence: 3; Percentage of agreement: 95.5%
The likelihood of PEI in patients with pancreatic head cancer and Comment: There is limited evidence to support the use of nutri-
in those who have undergone total pancreatectomy or pan- tional markers for diagnosing PEI due to the lack of an appropriate
creaticoduodenectomy is greater than 90%.41,59,60 In such cases, reference method. Single assessments of body weight, body mass in-
PERT can be initiated after assessing symptoms and nutritional dex, weight loss, lean body mass, and muscle mass are not sensitive
status, and pancreatic function evaluation (e.g., with fecal elastase enough for diagnosing PEI. Serial readings are more useful in this
[FE‐1]) can be avoided. 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‐
What is the role of symptoms in the diagnosis of PEI? albumin, may have diagnostic utility in PEI.62–73 However, strong
recommendations cannot be made due to the limited evidence.
Statement 2.3

In patients with pancreatic disease or a history of previous pancreatic How can exocrine pancreatic function be evaluated?
surgery, the diagnosis of PEI is supported by the presence of symp-
toms of malabsorption. However, these symptoms are neither sen- Statement 2.5
sitive nor specific to PEI, and additional nutritional evaluation and
pancreatic function testing may be required. The exocrine pancreatic function can be evaluated through direct
Level of evidence: 3; Percentage of agreement: 94.7% invasive tests that measure the stimulated pancreatic secretion in
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
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duodenal fluid or non‐invasive tests that quantify fecal pancreatic although a threshold of 200 μg/g is frequently used.58 The test is at
enzymes. Indirect non‐invasive tests can be used to evaluate the risk of producing false‐positive results in individuals with a low pre‐
effect of pancreatic enzyme deficiency on digestion. test probability and false‐negative results in those with a high pre‐
Level of evidence: 3; Percentage of agreement: 98.5% test probability. Whenever possible, the FE‐1 concentration should
Comment: Pancreatic secretion can be accurately evaluated by be measured in a formed stool sample to reduce the rate of false
bicarbonate and enzyme quantification in the duodenal fluid after positive results. The diagnosis of steatorrhea traditionally involves
intravenous administration of secretin and CCK. Duodenal contents the quantification of CFA. However, this test is cumbersome and
can be obtained using a nasoduodenal tube or endoscope.74,75 unpleasant and cannot differentiate between steatorrhea caused
However, this test is invasive and cumbersome and is rarely used in by PEI and other causes of fat malabsorption. The 13C‐MTG
clinical practice. An alternative method for quantifying pancreatic breath test is considered a suitable alternative to CFA for diag-
secretion is to measure the FE‐1 concentration. This test is nosing PEI and evaluating the effectiveness of PERT in clinical
frequently used in clinical practice. However, its accuracy for PEI is practice.78,79 However, this test is not widely available and may
low mainly because of its low levels of specificity and positive pre- produce false‐positive results in patients with non‐pancreatic
dictive value.58,76 Non‐invasive digestion tests are available, causes of fat malabsorption.
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. What is the role of radiological imaging in the
Both tests evaluate the digestive function of the pancreas; however, diagnosis of PEI?
false‐positive results may occur in patients with other causes of
maldigestion and fat malabsorption.77,78 Statement 2.8

PEI cannot be diagnosed using radiological imaging.

What is the role of direct invasive tests in the Level of evidence: 4; Percentage of agreement: 98.5%
diagnosis of PEI? Comment: Imaging with computed tomography (CT), magnetic
resonance imaging (MRI), or ultrasonography is not used to diagnose
Statement 2.6 PEI but is often used in patients with confirmed or suspected PEI to
determine the underlying causes. However, secretin‐enhanced mag-
Direct pancreatic function tests should not be used for the diagnosis netic resonance cholangiopancreatography (s‐MRCP) can qualita-
of PEI in clinical practice. tively and quantitatively assess pancreatic exocrine fluid
Level of evidence: 3; Percentage of agreement: 100% secretion.80,81 The clinical use of s‐MRCP is limited due to the lack of
Comment: Direct invasive tests accurately evaluate stimulated availability of secretin in many countries.
pancreatic secretion but do not assess the ability of secreted en-
zymes to digest ingested food. Therefore, in accordance with the
definition of PEI, direct invasive tests are not applicable. Can the clinical response to PERT be used to
diagnose PEI?

What is the role of non‐invasive tests for the Statement 2.9

diagnosis of PEI?
If the diagnosis of PEI cannot be established based on the combined
Statement 2.7 evaluation of symptoms, nutritional status, and pancreatic function,
assessing the clinical response to empirical PERT may be useful in the
Non‐invasive tests such as FE‐1 and 13C‐MTG breath tests are rec- appropriate clinical context.
ommended for assessing pancreatic exocrine function in clinical Level of evidence: 5; Percentage of agreement: 97.3%
practice. Comments: Diagnosing PEI can be challenging in some cases
Level of evidence: 2; Percentage of agreement: 98.5% owing to the low specificity of symptoms and nutritional deficiencies
Comment: The FE‐1 test is commonly used as a non‐invasive as well as the limited accuracy of the FE‐I test. Therefore, in patients
pancreatic function test. This test is widely available and requires with confirmed pancreatic disease, the evaluation of the clinical
only a small amount of stool sample for analysis. It is generally response to PERT in terms of symptom relief and nutritional
accepted that the lower the FE‐1 concentration, the higher the improvement may support the diagnosis of PEI. However, evidence
probability of PEI. However, a cut‐off for PEI cannot be established, supporting this approach is lacking.
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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CHAPTER 3: A GENERAL THERAPEUTIC APPROACH status, and the QoL in patients with CP88–90, and improves body
TO PEI weight and symptoms of maldigestion in patients with PC.39,41
No randomized clinical trials with sufficiently long durations have
What are the general indications for the treatment of evaluated the effect of PERT on the morbidity and mortality of pa-
patients with PEI? tients with PEI. However, because malnutrition is the primary clinical
consequence of PEI and has been linked to poor outcomes in various
Statement 3.1.1 PEI‐related diseases, it is reasonable to consider PERT as a treatment
for preventing PEI‐related morbidity and mortality.41,91–93
PEI should always be treated.
Level of evidence: 1; Percentage of agreement: 98.8%
What enzyme preparations can be used for the
treatment of patients with PEI?
Statement 3.1.2
Statement 3.3.1
PERT is indicated in patients with PEI secondary to CP, AP, PC, CF,
history of pancreatic surgery, and possibly other metabolic or Pancreatic enzyme preparations, particularly pancreatin, are the
gastroenterological conditions. recommended first‐line treatment for PEI.
Level of evidence: 1; Percentage of agreement: 90.3% Level of evidence: 1; Percentage of agreement: 98.8%
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 Statement 3.3.2
maldigestion, malabsorption, and impaired nutrient metabolism.83–85
Fat and protein absorptions increase significantly with PERT Small‐sized enteric‐coated pellets are the preferred pancreatin
86
compared with baseline or placebo. Further studies are needed to preparations for PEI.
evaluate the long‐term effects of PERT on the morbidity and mor- Level of evidence: 2; Percentage of agreement: 98.8%
tality in patients with PEI.

Statement 3.3.3
What are the general benefits of PERT in patients
with PEI? The most commonly used PERT preparations are of porcine origin.
Patients should be informed of the porcine origin of PERT before
Statement 3.2.1 initiating therapy.
Level of evidence: 5; Percentage of agreement: 95.2%
PERT enhances fat and protein absorption in patients with PEI. Comment: PERT is available in different preparations that vary
Level of evidence: 1; Percentage of agreement: 96.4% 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,
Statement 3.2.2 empty from the stomach with nutrients, and release enzymes rapidly
in the proximal small intestine.95,97 The particle size and size distri-
PERT positively affects body weight, nutritional status, symptoms, bution of pancreatic enzyme preparation pellets have implications for
and the QoL in patients with PEI. their clinical efficacy.98–100 Particles smaller than 2 mm may facilitate
Level of evidence: 1; Percentage of agreement: 98.8% 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
Statement 3.2.3 from gastric acidity by enteric coating, which disintegrates rapidly at
pH ≥ 5.5, in the duodenum to release them.94,100,105 Pharmacological
PERT may reduce morbidity and mortality in patients with PEI. inhibition of gastric acid secretion is required to avoid acid‐mediated
Level of evidence: 3; Percentage of agreement: 90.4% enzyme inactivation when uncoated enzyme preparations are used.
Comment: Two meta‐analyses on PEI secondary to CP reported PERT preparations with evidence of efficacy are of porcine origin. A
that PERT decreases fecal fat excretion and improves the CFA and non‐porcine PERT formulation was developed but failed to meet its
nitrogen absorption compared with baseline and placebo.39,86 PERT primary endpoint in a phase III clinical trial.106 Patients on special
87
reduces weight loss after AP , improves body weight, nutritional diets, such as vegans or vegetarians, and those with religious reasons
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
10
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may require non‐porcine preparations. Although plant‐based or 63%, respectively. It is important to note that the assessment was
fungal preparations are under development or available in some conducted on a small meal consisting of two pieces of toast with
countries, their efficacy has not yet been well established. butter and water and that a prokinetic was administered. No other
study has specifically addressed this administration schedule.39 Two
recent guidelines recommend distributing pancreatic enzymes with
What are the initial PERT doses for the treatment meals and snacks containing fat, protein, and polysaccharides
of PEI? (excluding disaccharide‐based foods such as sugar confectioneries
and most fruits).24,112
Statement 3.4

The initial doses of PERT vary mainly depending on the patient's age What is the definition of successful PERT?
(adult or child), severity of PEI, and fat content of the meal.
Level of evidence: 3; Percentage of agreement: 94.0% Statement 3.6.1
Comment: The dosages for PERT are based on lipase activity.
The initial dose of lipase into the duodenum should be approximately Successful PERT can be defined as the resolution of nutritional de-
10% of the physiologically secreted dose.24 However, randomized ficiencies and relief of symptoms and signs associated with PEI.
trials comparing different enzyme doses are lacking. Administration Level of evidence: 5; Percentage of agreement: 97.6%
of a minimum dose of 40,000–50,000 units of lipase with main meals
and half of that dose (20,000–25,000 units) with snacks has been
shown to be effective in adult patients.21,82 Some guidelines suggest Statement 3.6.2
starting with a lower dose of 25,000–40,000 units of lipase per
meal25,107; however, evidence for doses below 40,000 units is scarce. Some patients with PEI may not achieve complete treatment success
A higher starting dose of PERT has been reported to be effective in with PERT; however, even partial success may justify continued
patients with severe PEI, such as those who have undergone PERT. Partial success occurs when some of the symptoms/signs or
pancreaticoduodenectomy. nutritional deficiencies are resolved or improved in a clinically
The initial enzyme dose for children can be calculated based on meaningful way.
either body weight (500‐2500 lipase units/kg/meal) or meal fat con- Level of evidence: 5; Percentage of agreement: 97.6%
107–110
tent (500‐4000 units of lipase/g of fat/day). For infants, there is Comment: The above definition of treatment success has not
a lack of data; therefore, the initial dose of PERT is based on expert been tested in trials but is based on expert opinion. This suggests that
consensus. The administration of 5, 000 lipase units per breastfeed or successful PERT eliminates the abdominal symptoms caused by PEI
100–120 ml of infant formula is recommended.107,109,110 and that the patient achieves and maintains a normal nutritional
status. The primary outcome parameter used in most randomized
controlled trials on the efficacy of PERT is fat absorption, but CFA is
How should PERT be administered to patients not a suitable parameter to define treatment success in clinical
with PEI? practice.39,41,86 PERT increases serum nutritional parameters and
improves gastrointestinal symptoms and the QoL in affected pa-
Statement 3.5 tients.41 In patients with CF, improvement in nutritional status has
often been demonstrated to be a primary outcome parameter.113
PERT preparations should be taken with meals and snacks. Long‐term studies on PERT demonstrated clinically relevant and
Level of evidence: 2; Percentage of agreement: 95.1% statistically significant improvements in nutritional parameters,
Comment: To ensure the efficacy of pancreatic enzyme supple- including body weight and PEI‐related symptoms, after 6–
ments, it is necessary to mix them with chyme to simulate the action 12 months.88,114–116 Some patients may experience symptoms of
31
of endogenous pancreatic enzymes. Prandial enzyme administra- maldigestion with PERT, but there is a significant improvement in
tion has been proven as effective as hourly administration in diarrhea, steatorrhea, weight loss, recurrent pain, and the overall
1
decreasing steatorrhea. A recent randomized three‐way crossover QoL.88,89 The proportion of patients with micronutrient deficiencies
study compared three regimes of pancreatic enzyme administration: on PERT remains unknown.88 In patients with CF, PERT is associated
schedule A (immediately before meals), schedule B (immediately after with an improvement in essential nutritional parameters. However,
meals), and schedule C (distributed along with meals).111 The per- long‐term studies on this topic are lacking. For patients with PC,
centages of patients who achieved normalized fat digestion under there is an increasing evidence that PERT is associated with survival
therapy with schedules A, B, and C were found to be 50%, 54%, and benefit and may improve the QoL.41,117
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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What is the approach to patients with insufficient chronic hepatitis E virus infection in lung transplant recipients with
response to PERT? CF.128 However, most studies involving PERT have found that
treatment‐emergency adverse events are similar to those of placebo
Statement 3.7 and are generally consistent with the underlying disease.39,129,130
Additionally, no drug interactions have been identified to date.131
Patients who do not respond or partially respond to PERT should be The use of high doses of pancreatic enzymes in older patients
evaluated for adherence problems and inadequate PERT adminis- with CF may increase the risk of fibrotic colonopathy.131,132 This has
tration. Enzyme dose escalation and/or additional treatment with a been related to enzyme coatings containing methacrylic acid co-
proton pump inhibitor (PPI) should be provided on an individualized polymers but has also been described in patients who are not on
basis along with testing to rule out other diseases. PERT.126,130,133 In children with CF, hyperuricosuria has been
Level of evidence: 4; Percentage of agreement: 98.8% described as dose‐dependent because of the high purine content of
Comment: For patients who do not respond to PERT, treatment the drug. Therefore, PERT should be used with caution in patients
adherence and proper PERT administration should be confirmed. with gout, hyperuricemia, or renal impairment.126
Implementation of the next steps should be personalized, including
dose‐escalation89,118–120 and/or the addition of a PPI.121–124 The
PERT dose should be increased stepwise to double or triple the initial How should PERT be applied to particular situations?
dose to achieve an appropriate therapeutic response. However, the
maximum enzyme dose has not yet been determined. PPI can be Statement 3.9.1
added to optimize enzyme release and improve enzyme activity in
patients with acidic intraluminal pH.55 Comorbid diseases associated There is no evidence indicating any harmful effects of PERT during
with gastrointestinal symptoms that can mimic PEI, such as intestinal pregnancy or lactation.
bacterial overgrowth, celiac disease (CeD), food intolerances, irrita- Level of evidence: 4; Percentage of agreement: 97.6%
ble bowel syndrome (IBS), inflammatory bowel disease (IBD), giar-
diasis, drug‐induced diarrhea, bile acid malabsorption, microscopic
colitis, and colorectal cancer should be excluded in patients with Statement 3.9.2
insufficient response to PERT and PPI.50,66,125
If required, PERT can be added to enteral nutrition; however, its
efficacy has not yet been proven.
What adverse events may be associated with PERT? Level of evidence: 4; Percentage of agreement: 94.0%

Statement 3.8.1
Statement 3.9.3
PERT is not associated with major adverse effects, and most reported
symptoms are consistent with the underlying disease. Currently, there is no viable alternative to PERT for patients who
Level of evidence: 1; Percentage of agreement: 100% avoid porcine derivatives.
Level of evidence: 3; Percentage of agreement: 92.8%

Statement 3.8.2
Statement 3.9.4
Close monitoring is necessary for patients with CF and PEI on high‐
dose PERT or those with comorbidities because of potential adverse For patients with dysphagia, PERT products should be suspended in
effects. acidic and puree‐consistent food.
Level of evidence: 4; Percentage of agreement: 96.8% Level of evidence: 5; Percentage of agreement: 95.2%
Comment: Few studies have reported that high doses of Comment: Clinical trials of PERT for PEI do not include pregnant
pancreatic extracts may induce symptoms such as nausea, con- or lactating women. Case reports of CF and other diseases do not
stipation, and diarrhea, which are linked to transient intestinal up- suggest any adverse events associated with PERT during preg-
set.126 Other symptoms, such as pruritus, urticaria, rash, blurred nancy.134–136 By contrast, essential fatty acids and other nutrients
vision, myalgia, muscle spasm, and asymptomatic elevation of liver are necessary for development during early gestation; therefore,
enzymes, have rarely been reported. These symptoms may be related discontinuing PERT may be counterproductive.137
127
to the hypersensitivity to these products. There is also a theo- PERT efficacy studies are typically conducted in patients
retical concern regarding the potential viral transmission with prep- receiving oral nutrition. However, in patients with PEI who require
arations using porcine formulations; however, this has not been enteral nutrition, PERT must be administered through feeding tubes.
86
confirmed. More recently, porcine‐derived PERT was linked to In such cases, the delivery method should be modified to allow gastric
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or jejunal administration and continuous or bolus feeding.138 En- of patients with PEI. In malnutrition cases, an excessively restricted
zymes can be combined with food and administered immediately diet may be counterproductive. Patients with PEI should be advised
139,140
after mixing. Using liquid pancreatic enzymes, 125,000– to consume a varied healthy diet and take an adequate dose of PERT.
250,000 units of lipase are required to achieve complete lipolysis in As PEI progresses and clinical symptoms become more challenging to
1000 ml of polymeric feed compared with 37,500 units in 1000 ml of manage, limiting fat intake may be beneficial if other causes of fat
a peptide/semi‐elemental product.141 Cartridges containing lipase intolerance, such as bile acid malabsorption, are ruled out.24
and designed to connect to enteral nutrition systems have been Consuming smaller portions and eating more frequently throughout
developed, but comparative studies on the addition of PERT to food the day can enhance the efficacy of PERT; however, the evidence is
are lacking. lacking. Restricting dietary fiber intake may alleviate malabsorptive
Some individuals who follow vegan or vegetarian diets or who symptoms in patients with PEI because fiber can bind to lipase,
are of Jewish or Muslim faith may request a non‐porcine alternative thereby reducing its availability.105
to PERT. Liprotamase is available in some countries as a non‐animal‐ Patients with PEI should have access to a specialist dietitian
derived alternative.142 specifically educated on pancreatic disorders.24,27,107,143,144 Dietary
The intake of PERT capsules may be challenging in patients with counseling by a specialist dietitian results in improved anthropo-
dysphagia. Although evidence is lacking, there is a consensus that metric measurements, less pain, and improved fat absorption in pa-
PERT can be suspended in acidic puree‐consistent foods when cap- tients with PEI. In addition, patients receive PERT more frequently
sules cannot be taken.27 and do not require artificial supplementation if guided by specialist
dietitians.145,146 Patients with PC and PEI who were able to improve
their nutritional status showed significant improvements in their QoL
What dietary interventions are recommended for and survival.129 Despite this, management by nonspecialist dietitians
patients with PEI? who provide inadequate advice is common.115,116,147
Data on enteral interventions for PEI are lacking. Evidence sug-
Statement 3.10.1 gests that enteral feeds that are peptide‐ or MCT‐based may provide
benefits in terms of weight maintenance and shorter hospital stays
PERT should be optimized to allow as normal a diet as possible. than standard polymeric feeds in patients with severe AP.148
Level of evidence: 5; Percentage of agreement: 98.8%

CHAPTER 4: PEI SECONDARY TO CP

Statement 3.10.2
Question: 4.1. what is the prevalence of PEI in
If PEI symptoms persist despite apparently adequate PERT, it may be patients with CP?
necessary to restrict dietary fiber intake, especially in patients on a
high‐fiber diet. Statement 4.1.1
Level of evidence: 4; Percentage of agreement: 86.8%
The prevalence of PEI in CP is 20%–90%, depending on the duration,
severity, and etiology of the disease.
Statement 3.10.3 Level of evidence 4; Percentage of agreement: 98.5%

Patients diagnosed with PEI should access experienced dietitians for

nutritional care. Statement 4.1.2
Level of evidence: 4; Percentage of agreement: 94.0%
Based on clinical criteria and/or non‐invasive tests, the reported
pooled prevalence of PEI in patients with autoimmune pancreatitis
Statement 3.10.4 (AIP) is approximately 45%.
Level of evidence: 3; Percentage of agreement: 90.5%
For patients with PEI receiving enteral nutrition, peptide‐ and Comment: Depending on the severity and etiology of CP, PEI has
medium‐chain triglyceride (MCT)‐based formulas may be worth been reported in 30%–85% of patients with CP within the first 10–
considering if they are intolerant to standard polymeric feeds. 15 years after diagnosis, with a marked increase later.149 Large studies
Level of evidence: 5; Percentage of agreement: 91.6% show a prevalence of PEI ranging 50%–75%, particularly in patients
Comment: Patients with PEI receiving adequate PERT usually do with alcohol‐induced CP and prolonged disease.150 Data from the
not require dietary fat restriction. No studies have evaluated the Scandinavian Baltic Pancreatic Club study reflect a 68% prevalence of
effect of dietary fat restriction on the nutritional or clinical outcomes PEI in patients with CP,151 with clinically significant PEI developing in
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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60%–90% of patients within a decade of diagnosis, with alcoholic CP, What is the treatment of PEI in patients with CP?
hereditary factors, and smoking increasing the risk of PEI.152 In addi-
tion, a recent study showed that PEI was more common in patients with Statement 4.5
longer duration of CP, with the prevalence of PEI increasing from 20%
after 5 years to 70% after 20 years of disease.153 PEI treatment in patients with CP follows general recommendations
No studies have evaluated the prevalence of PEI in patients with (see Chapter 3).
AIP using digestive tests, such as the CFA. A meta‐analysis by Lan- Level of evidence: 1; Percentage of agreement: 100%
zillota et al. reported a 45% prevalence of PEI at the time of AIP
diagnosis, based on clinical criteria and/or non‐invasive tests.154 The
prevalence decreased to 36% during follow‐up. A retrospective What are the benefits of PERT in patients with PEI
cohort study from Sweden reported low fecal elastase concentra- secondary to CP?
tions in 72.7% of patients at diagnosis of AIP and 63.5% during
follow‐up, with no significant effect of pharmacological treatment.155 Statement 4.6.1

PERT improves digestion and nutrient absorption in patients with PEI

What is the specific pathogenesis of PEI in patients secondary to CP.
with CP? Quality of evidence: moderate; Recommendation: strong (Grade
1B); Percentage of agreement: 100%
Statement 4.2

PEI in patients with CP results from loss of function of the pancreatic Statement 4.6.2
parenchyma and/or obstruction of the pancreatic duct.
Level of evidence: 1; Percentage of agreement: 98.5% PERT improves the QoL of patients with PEI secondary to CP.
Comment: CP is a progressive IBD that causes the loss and Level of evidence: 4; Percentage of agreement: 98.5%
fibrosis of functional pancreatic tissues, resulting in a decrease in the
synthesis and secretion of pancreatic enzymes. Based on classic
studies by Di Magno et al., the amount of enzyme‐rich fluid secreted Statement 4.6.3
by the pancreas is approximately 10 times higher than that required
for normal digestion. Therefore, although subtle changes in exocrine The extent to which PERT can reduce mortality is unclear; however,
function can be detected in patients with early pancreatic disease, it is likely to reduce long‐term morbidity in patients with PEI sec-
overt steatorrhea as a manifestation of PEI only occurs when enzyme ondary to CP.
1
secretion is reduced by more than 90%. In addition to the loss of Level of evidence: 3; Percentage of agreement: 93.9%
pancreatic parenchyma, PEI can be caused by main pancreatic duct
obstruction owing to stenosis or calcification.14,15
Statement 4.6.4

How should PEI be diagnosed in patients with CP? Similar to other causes of PEI, PERT is associated with few adverse
events and is well‐tolerated in patients with PEI secondary to CP (see
Statement 4.3 chapter 3).
Quality of evidence: high; Recommendation: strong (Grade 1A);
The diagnosis of PEI in patients with CP follows general recom- Percentage of agreement: 100%
mendations (see Chapter 2). Comment: Meta‐analyses by Gan et al.86 and de la Iglesia et al.39
Level of evidence: 1; Percentage of agreement: 100% showed that PERT significantly improves fat absorption and reduces
fecal fat excretion in patients with CP. However, in some patients with
CP and PEI, fat absorption is not fully normalized on the standard dose
What are the clinical consequences of PEI in patients of PERT, with fecal fat excretion ranging 13–25 g/day (normal <7.5 g/
with CP? day). PERT reduces fecal nitrogen excretion, a sign of protein malab-
sorption.39 A significant reduction in fecal weight is also observed.
Statement 4.4 PEI‐related malnutrition and abdominal symptoms, such as
excessive bloating and steatorrhea, affect the QoL of patients with
The clinical consequences of PEI in CP are similar to those of other CP. Although most studies on PERT have been short‐term, there is
causes of PEI (see Chapter 1). evidence of a positive impact on QoL. A large, 1‐year, multicenter
Level of evidence: 1; Percentage of agreement: 98.6% study showed that PERT significantly reduces recurrent abdominal
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pain and gastrointestinal symptoms and improves the gastrointes- clinical, and biochemical monitoring.24,27,112,166 Monitoring should
tinal QoL (GIQL) index, with improvements across several domains.89 include nutritional screening using tools such as the Nutritional Risk
This positive effect of PERT on the QoL of patients with CP and PEI Index or Malnutrition Universal Screening Tool,167,168 body weight,
90
has been confirmed in other studies. Specific tools for measuring maldigestion‐related symptoms, and key biochemical markers such as
PEI‐related QoL are scarce, but a recent study introduced a new complete blood count, glucose status, plasma proteins, and fat‐
patient‐reported outcome measure, the PEI‐Q, which correlates well soluble vitamins. Therefore, other assessments should be tailored
156
with GIQL scores. to individual needs. To prevent significant clinical and nutritional
A consensus in national and international guidelines recognizes decline, a suggested frequency of 6‐month assessment is suggested,
PEI‐related maldigestion as a risk factor for increased morbidity and with particular attention paid to pain management and PERT
mortality in patients with CP.8,27 This consensus is based on a adherence.
fundamental understanding of digestive and nutritional deficiencies
associated with PEI as evidenced in several studies.31 Osteoporosis,
often associated with CP, is a potential long‐term morbidity outcome CHAPTER 5: PEI AFTER AP
in which PERT plays a critical role by improving the absorption of
fat‐soluble vitamins including vitamin D.157 What is the prevalence of PEI in patients after AP?
Observational research has also suggested an association between
PEI and mortality in patients with CP.91 Indirect evidence that PERT Statement 5.1
may improve long‐term outcomes, including mortality, comes from an
observational study in which the absence of PERT prescription at The pooled reported prevalence of PEI after AP is 27%–35%. PEI is
hospital discharge after surgery for CP was associated with an more common in patients with severe forms of AP, in those with
increased risk of mortality over a follow‐up period of 5.3 years.158 extensive pancreatic necrosis, and after AP in those with alcohol
The safety profiles of PERT in four placebo‐controlled trials abuse.
have shown controversial results.129,159–161 Adverse events, mainly Level of evidence: 4; Percentage of agreement: 98.4%
mild gastrointestinal symptoms such as abnormal stools, bloating, Comment: Pooled data showed a prevalence of PEI of up to 62% at
abdominal pain, and vomiting, were commonly reported in all admission for AP, with a significant decrease to 27%–35% at follow‐
studies.129,159,160 A 2001 randomized controlled trial highlighted up.40,169 A higher prevalence of PEI has been observed in patients
significant glycemic control problems associated with starting or with alcoholic AP, possibly due to preexisting pancreatic damage
stopping PERT in patients with diabetes.162 Recent studies suggest caused by alcohol.170 Patients with necrotizing AP have a higher
that such serum glucose disturbances are rare and not higher in prevalence of PEI than those with interstitial AP (18.9%–24% vs.
patients undergoing PERT than in controls.159 24.8%–47.0%), but the extent of necrosis (more or less than 50% of the
Long‐term studies have reported mild adverse events, with gland) was not significantly associated with the prevalence of PEI.40
88,90
gastrointestinal symptoms being the most common. Serious The prevalence of PEI is lower in patients with mild AP (19.4%–22.7%)
events are rare and unrelated to the treatment. Fibrosing colon- than in those with severe CP (30.0%–33.4%).169 Patients who undergo
opathy, a serious complication of PERT, has been reported in chil- necrosectomy tend to have a higher prevalence of PEI after AP (rela-
dren with CF but not in those with CP.163 tive risk 1.62; 95% confidence interval [CI] 0.77–3.44). The prevalence
of PEI depends on the diagnostic method, with direct functional
tests indicating PEI in 41.7% of patients after AP, compared with 24.4%
How should patients with PEI secondary to CP be when indirect tests are used. Given the limited sensitivity of the FE‐1
monitored? test for mild‐to‐moderate reductions in pancreatic secretions, the
true rate of PEI after AP may be underreported.57
Statement 4.7

In patients with PEI secondary to CP, a structured assessment What is the specific pathogenesis of PEI in patients
including clinical symptoms, nutritional status, and biochemical pa- with AP?
rameters is suggested (Table 2). The frequency of assessment varies
depending on the clinical situation of the patient and the disease Statement 5.2
severity.
Level of evidence: 4; Percentage of agreement: 91.1% The pathogenesis of PEI in patients with AP is not completely un-
Comment: Patients with PEI secondary to CP are at risk of derstood; however, the loss of pancreatic acinar tissue due to ne-
164
gastrointestinal symptoms and nutritional deficiencies. There is a crosis, ductal stenosis, or leakage may be associated with this
significant unmet need for standardized guidance on the manage- complication.
ment of gastrointestinal symptoms, diet, and digestion in these pa- Level of evidence: 5; Percentage of agreement: 96.9%
tients and their caregivers.165 Although long‐term data on structured Comment: The development of PEI after AP correlates with dis-
follow‐up are lacking, expert guidelines advocate regular nutritional, ease severity,40,169,171,172 presence and extent of necrosis,40,171,173
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
- 15

T A B L E 2 Suggested parameters for long‐term follow‐up of patients with pancreatic exocrine insufficiency and CP (according to British‐,
ESPEN‐, DGVS‐, and UEG guidelines).

Nutritional/Functional Biochemical Clinical Dietary

Body weight Full blood count Compliance with treatment Food avoidance owing to abdominal
and iron reserves symptoms
BMI

Weight loss

Anthropometric Plasma proteins Assessment of bowel symptoms: stool 24‐h dietary recall with relevant PERT dose
‐ Mid‐arm muscle circumference ‐ Albumin frequency and color to assess adherence and ratio of PERT with
‐ Muscle mass quantification (bio- ‐ Prealbumin ‐ Presence of abdominal bloating/wind nutrition
impedance and CT scan) every 2 ‐ Retinol‐ ‐ Postprandial abdominal pain
years binding protein
‐ DXA scan for bone and body ‐ Transferrin
composition every 2 years Micronutrient
‐ Grip strength status
‐ Magnesium
‐ Fat‐soluble
vitamins
‐ Zinc, selenium
‐ Vitamin B12
and folate

6‐min walking test CRP Factors impacting QoL Avoidance of fat‐containing products

Glucose and Change in medication (especially opioids and Nutritional adequacy of diet
HbA1c anti‐emetic/anti‐diarrheal medications)

Parathyroid Implementation of lifestyle advice (smoking

hormone and alcohol cessation, weight‐bearing
exercise, and sunlight exposure)

Abbreviations: CP, chronic pancreatitis; CRP, C‐reactive protein; CT, computed tomography; DGVS, German Society for Digestive and Metabolic
Diseases; DXA, dual‐energy X‐ray absorptiometry; ESPEN, European Society for Clinical Nutrition and Metabolism; HbA1c, hemoglobin A1c; PERT,
pancreatic enzyme replacement therapy; QoL, quality of life; UEG, United European Gastroenterology.

alcoholic etiology,40,169,174,175 and invasive treatments such as alcoholic etiology. Although previously normal, screening for PEI
necrosectomy.169,176,177 PEI often results from the loss of exocrine should be repeated if symptoms attributable to PEI are present.
pancreatic tissue owing to inflammation, necrosis, surgery, or long‐ Level of evidence: 5; Percentage of agreement: 87.5%
term alcohol consumption. In addition, PEI is more common in cases Comment: As mentioned above, approximately 62% of patients
where the main pancreatic duct is not visible or is only partially visible develop PEI upon admission with AP, and about one third of patients
on imaging,176,178 suggesting that ductal complications, such as stric- have persistent PEI during follow‐up. These figures support screening
tures or leaks that impede the flow of pancreatic juice, contribute for PEI in patients after AP, especially in those with severe necro-
to PEI. tizing disease or alcoholic etiology.40,169

How should PEI be diagnosed specifically in patients

with AP? Is a delay after AP recovery recommended to confirm
the diagnosis of PEI?
Statement 5.3
Statement 5.5.1
The diagnosis of PEI in patients with AP follows general recommen-
dations (see Chapter 2). No delay is recommended in confirming the diagnosis of PEI after
Level of evidence: 3; Percentage of agreement: 100% recovery from AP.
Level of evidence: 5; Percentage of agreement: 90.3%
Which patients with/after AP should be tested
for PEI?
Statement 5.5.2
Statement 5.4
In patients with PEI after AP, rescreening for PEI during follow‐up is
All patients should be screened for PEI after an episode of AP, recommended to re‐evaluate the need to maintain PERT.
particularly those with severe disease, pancreatic necrosis, or Level of evidence: 5; Percentage of agreement: 90.3%
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
16
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Comment: There is a debate about whether pancreatic injury in the hospital, less weight loss, and an increase in the QoL compared
causing PEI in AP is temporary or permanent.179,180 A study of with those who received placebo.87 This study suggests the impact of
370 patients at admission and 1795 at follow‐up reported a PEI and its treatment during AP; however, stronger evidence is
decrease in the prevalence of PEI from 62% at admission to 35% lacking.
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 What is the treatment of PEI in patients after AP?
PEI and potentially discontinue PERT, re‐testing for PEI at 3‐
month intervals after discharge is recommended. To rule out PEI Statement 5.9
resolution, it is recommended that those who remain on PERT be
retested (e.g., at 6 and 12 months).40 PEI treatment after AP follows general recommendations (see
Chapter 3).
Level of evidence: 1; Percentage of agreement: 98.5%
Is there any scenario in which empirical treatment for
PEI can be started without diagnostic tests?
Should PERT be added to enteral nutrition in patients
Statement 5.6 with AP?

Empirical treatment may be considered in the presence of symptoms Statement 5.10

of maldigestion or nutritional deficiencies, particularly after severe
necrotizing pancreatitis. A clear response can be both diagnostic and PERT can be added to enteral nutrition in patients with severely
therapeutic in PEI. necrotizing AP; however, data on its efficacy and feasibility are
Level of evidence: 5; Percentage of agreement: 95.3% scarce.
Comment: Since the main goals of PEI therapy are to relieve Level of evidence: 4; Percentage of agreement: 93.5%
gastrointestinal symptoms and improve the nutritional status of pa- Comment: For patients with PEI receiving enteral nutrition,
tients, empirical PERT may be considered in some patients after PERT can be administered via a feeding tube that requires adjust-
AP.181 In cases with a high probability of PEI, such as patients with ments for gastric or jejunal delivery and is suitable for both contin-
severe necrotizing pancreatitis, the negative predictive value of FE‐1 uous and bolus feeding methods.27 Clinical improvements were
as a pancreatic function test for the diagnosis of PEI is not strong observed when PERT was combined with enteral nutrition and used
enough to avoid starting empirical PERT. immediately.112 Enzymes can be introduced into the feeding tube
every 2 h or added directly to the formula.27

What are the clinical consequences of PEI in patients

with AP? What are the specific benefits of PERT in patients
with AP?
Statement 5.7
Statement 5.11
The clinical consequences of PEI in patients with AP are comparable
with those with other PEI etiologies (see Chapter 1). PERT is likely to relieve the symptoms of maldigestion and prevent
Level of evidence: 1; Percentage of agreement: 96.9% nutritional deficiencies in patients with PEI after AP. However, spe-
cific data are lacking. There is insufficient evidence to support the use
of PERT for PEI during admission for AP.
Is PEI associated with delayed recovery after AP? Level of evidence: 5; Percentage of agreement: 93.8%
Comment: In a study by Kahl et al., patients who underwent
Statement 5.8 PERT tended to have better outcomes, but these improvements
were not statistically significant. There was a positive trend in all
PEI may affect functional recovery, length of hospital stay, and the QoL subscores associated with enzyme supplementation.87 It should
QoL during the early post‐AP period. be noted that the sample size of this study was small, which limited
Quality of evidence: moderate; Recommendation: weak (Grade 2B); the significance of the results. Similarly, Patankar et al. found no
Percentage of agreement: 92.3% significant differences in laboratory or clinical outcomes, including
Comment: In a double‐blind randomized controlled trial of pa- total pain scores and analgesic requirements, between the groups.182
tients with abnormally low FE‐1 test results in the early phase of AP, The length of hospital stay was comparable between the placebo and
those who received PERT tended to recover faster, with fewer days PERT groups.
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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How should patients with PEI secondary to AP be What is the pathogenesis of PEI in patients with PC?
monitored?
Statement 6.2
Statement 5.12
PEI in PC is primarily caused by tumor obstruction of the
In patients with PEI secondary to AP, and as a general recommen- main pancreatic duct. Atrophy, replacement of the pancreatic pa-
dation, clinical symptoms, nutritional status, a non‐invasive test for renchyma, and loss of pancreatic exocrine tissue may also play roles.
PEI (e.g., FE‐1), and adherence to PERT can be monitored at 3, 6, and Level of evidence: 1; Percentage of agreement: 93.6%
12 months after hospital discharge, and then every 6–12 months in Comment: The main causes of PEI in patients with PC are
the case of persistent PEI. obstruction of the main pancreatic duct with subsequent paren-
Level of evidence: 5; Percentage of agreement: 92.1% chymal atrophy proximal to the obstruction and loss of exocrine
Comment: No prospective randomized trial has reported the pancreatic tissue or its replacement by tumors and fibrotic tis-
benefit of individualized monitoring in patients with PEI after an sue.41,183,185–187 This obstruction impedes the flow of pancreatic
episode of AP. As pancreatic function may recover in the first few enzymes and bicarbonates necessary for neutralizing gastric
months after AP, this assessment can be performed at the end of the acid.186 A double‐blind, prospective, randomized, single‐center
acute episode and then at 3, 6, and 12 months. If the assessment shows interventional study concluded that pancreatic endoscopic
that exocrine pancreatic function has returned, further assessment can drainage was associated with a significant improvement in exocrine
be stopped; however, if there is continuing evidence of PEI, monitoring pancreatic function in patients with unresectable PC, supporting
should be continued at 6–12 months intervals. Monitoring includes the major role of ductal obstruction in the pathogenesis of PEI in
clinical symptoms, FE‐1 concentrations, compliance with PERT, and patients with PC.183
nutritional status. Further detailed recommendations for nutritional
assessment in PEI can be found in the recent ESPEN guidelines.112
How can PEI be diagnosed in patients with PC?

CHAPTER 6: PEI ASSOCIATED WITH PC Statement 6.3

What is the prevalence of PEI in patients with PC? Diagnosis of PEI in patients with PC follows general recommenda-
tions (Chapter 2).
Statement 6.1.1 Level of evidence: 3; Percentage of agreement: 96.9%

PEI occurs in approximately 70% of patients with PC. It is more

common in patients with tumors located in the pancreatic head and
What are the clinical consequences of PEI in patients
in those with advanced‐stage disease.
with PC?
Level of evidence: 1; Percentage of agreement: 100%

Statement 6.4.1
Statement 6.1.2
PEI contributes to malnutrition and weight loss in patients with PC.

The prevalence of PEI in patients with advanced PC increases with Level of evidence: 3; Percentage of agreement: 100%

disease progression.
Level of evidence: 4; Percentage of agreement: 98.4%
Comment: According to a meta‐analysis, the pooled prevalence Statement 6.4.2
41
of PEI in advanced PC is 72% (95% CI: 55%–86%), with significantly
higher prevalence in tumors located in the pancreatic head (RR: 3.36, PEI increases the risk of sarcopenia in patients with PC, which is
95% CI: 1.07–10.54).41 In a study using the 13C‐MTG breath test, associated with a poor prognosis.
the prevalence of PEI in patients with unresectable PC was 80%. 183 Level of evidence: 3; Percentage of agreement: 96.7%
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 Statement 6.4.3
59
patients with locally advanced PC.
A study of patients with a pancreatic head tumor showed that The severity of PEI based on the FE‐1 test is correlated with survival
the prevalence of PEI at diagnosis was 66%, rising to 92% after a in patients with advanced PC.
median follow‐up of 2 months.184 Level of evidence: 3; Percentage of agreement: 89.7%
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
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Statement 6.4.4 Statement 6.6.3

Untreated PEI affects the QoL in patients with PC. PERT may positively affect overall survival in patients with PEI sec-
Level of evidence: 4; Percentage of agreement: 93.6% ondary to PC.
Comment: Weight loss in patients with PC is often caused by Level of evidence: 2; Percentage of agreement: 91.8%
multiple factors, including PEI, which leads to potential nutritional Comment: In a pilot study, PERT significantly improved symptoms
deficiencies. The patients with PEI tend to have lower albumin as measured by standardized QoL questionnaires. After 1 week of
levels.188 A higher, although not statistically significant, prevalence of PERT, the calculated diarrhea scores, pancreatic pain, and liver pain
PEI has been reported in malnourished or at‐risk patients (42.7%) improved significantly. After 3 weeks, there were significant im-
compared to their well‐nourished counterparts (26.7%) prior to provements in pancreatic pain and bloating/gas symptoms.193 In a
pancreaticoduodenectomy.189 In addition, a mouse model showed retrospective analysis of patients with advanced PC receiving first‐line
that the reduced exocrine pancreatic function associated with PC gemcitabine/nab‐paclitaxel, PERT significantly reduced floating or
contributes to adipose tissue loss.190 greasy/fatty stools at 3 months compared with controls. In addition,
PEI is associated with sarcopenia in patients with pancreatic PERT doubled the number of patients who gained weight during the
68
diseases, including cancer. Sarcopenia, particularly during chemo- treatment.194
191
therapy, is a predictor of poor survival in patients with PC. Sar- In a randomized controlled trial of patients with inoperable
copenia in patients undergoing surgery for PC is associated with a pancreatic head cancer, PERT significantly helped maintain body
higher incidence of postoperative complications, higher 30‐day weight, which was associated with a significantly higher total daily
192
mortality rates, and reduced overall survival. energy intake, whereas the placebo resulted in weight loss over
In the study by Partelli et al., FE‐1 ≤20 μg/g was an independent 8 weeks. The CFA increased by 12% in the PERT group and
predictor of survival in patients with advanced PC. Median overall decreased by 8% in the placebo group (50). However, two random-
survival was significantly longer in patients with FE‐1 >20 μg/g ized controlled trials involving patients with unresectable PC found
(11 months) than in those with FE‐1 <20 μg/g (7 months).188 no benefit of PERT for >8 weeks on body weight, nutritional markers,
The negative effect of PEI on QoL has been demonstrated using a subjective global assessment, or survival.195 A meta‐analysis of three
115
structured questionnaire for patients with PC or their caregivers. available randomized controlled trials showed only a trend toward a
In this study, digestive symptoms and difficulties in managing diet benefit for weight change with PERT.196
were identified as significant problems. These factors negatively Retrospective data support the survival benefits of PERT in pa-
affect the QoL, increase feelings of social isolation, and contribute to tients with PC.92,185 A meta‐analysis of prospective and retrospective
caregiver distress. 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
What is the treatment of PEI in patients with PC?

Statement 6.5 How should patients with PEI secondary to PC be

monitored?
Treatment of PEI in PC follows general recommendations (Chap-
ter 3). Statement 6.7
Level of evidence: 3; Percentage of agreement: 93.8%
Patients with PC and PEI should be monitored regularly to ensure
that they receive adequate management advice and that their
What are the benefits of PERT in patients with PC? symptoms are controlled. These patients should be reassessed
regularly to ensure that they do not require enzyme dose escalation
Statement 6.6.1 or nutritional support for anemia or other micronutrient deficiencies.
Level of evidence: 4; Percentage of agreement: 95.1%
PERT improves PEI‐related symptoms in patients with PC. Comment: After the initiation of PERT, patients with PEI should
Level of evidence: 3; Percentage of agreement: 100% 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 assess-
Statement 6.6.2 ment.27 A small qualitative study of patients who started PERT after
pancreaticoduodenectomy reported persistent diarrhea and poor
PERT can improve the nutritional status of patients with PC. adherence to the PERT prescription information.197 Further quali-
Level of evidence: 1; Percentage of agreement: 98.4% tative work with patients and their caregivers found that a lack of
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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information and advice on managing PEI was the most important etiologies confounded,149,198,208 and 17–39%209 in inherited forms of
unmet need and had a significant impact on the QoL.115 CP. Specific data for patients with CFTR‐RD are missing.

CHAPTER 7: PEI IN CF AND CFTR‐RELATED What is the specific pathogenesis of PEI in patients
DISORDERS (CFTR‐RD) with CF and CFTR‐RD?

What is the prevalence of PEI in CF and CFTR‐RD? Statement 7.2.1

Statement 7.1.1 Exocrine pancreatic function in patients with CF is affected by duct

obstruction and progressive damage, with consequent loss of func-
PEI occurs in 75%–90% of patients with CF. tional pancreatic parenchyma.
Level of evidence: 1; Percentage of agreement: 96.49% Level of evidence: 2; Percentage of agreement: 96.6%

Statement 7.1.2 Statement 7.2.2

The type of CFTR mutation determines the risk of PEI in patients with CFTR mutations are a significant contributor to PEI in patients with or
CF. Patients with severe biallelic (classes I, II, III, and VI) CFTR mu- without CF.
tations develop PEI early in life. Level of evidence: Level 1 (CF)—Level 4 (CFTR‐RD); Percentage of
Level of evidence: 1; Percentage of agreement: 96.5% agreement: 96.6%
Comment: Reduced or nonexistent CFTR channel function results
in reduced volume of pancreatic juice and hyperconcentration of
Statement 7.1.3 macromolecules. This can lead to protein precipitation in the duct
lumen causing obstruction, progressive pancreatic damage, and
Patients with pancreatic sufficient (PS)‐CF who develop pancreatitis pancreatic atrophy.204,210 Pancreatic diseases in patients with CF
have an increased risk of developing PEI over time. begin in utero and continue after birth. In CFTR‐RD, specific clinical
Level of evidence: 3; Percentage of agreement: 96.5% features linked to CFTR dysfunction in which CF has been ruled out and
carrying evidence of partially functioning CFTR protein,211 PEI can
appear due to reduced CFTR function or acute recurrent or CP.212
Statement 7.1.4

PEI has a wide prevalence in patients with CFTR‐RD, with CP being How can PEI be diagnosed in patients with CF and
the most common cause. those with CFTR‐RD?
Level of evidence: 3; Percentage of agreement: 96.5%
Comment: Clinical studies have established an 80%–90% prev- Statement 7.3
alence of PEI in patients with CF,108,198,199 and only a small number
maintain pancreatic function. In general, patients with CF develop The diagnosis of PEI in patients with CF follows general recom-
PEI early in life, with the majority occurring before 1 year of age.200 mendations (Chapter 2).
201,202
PEI is correlated with the genotype in patients with CF. In- Level of evidence: 1; Percentage of agreement: 98.3%
dividuals with two severe CFTR mutations (classes I, II, III, and VI)
tend to develop PEI early, whereas those with two mild CFTR mu-
tations (classes IV and V) or one severe and one mild mutation tend As from when and how frequent should PEI be
to develop PS at birth.108,199,200,203,204 Alleles belonging to classes screened in patients with CF and CFTR‐RD?
IV‐V are supposed to have some residual chloride channel activity at
the epithelial apical membranes; thus, these patients maintain re- Statement 7.4.1
sidual pancreatic function to be PS. However, cohort studies have
shown that patients with PS‐CF with recurrent episodes of pancre- In patients with CF:
atitis are at an increased risk (odds ratio[OR] 5.5) of developing PEI The confirmation of PEI is required as soon as CF is diagnosed. A
over time.205 Patients with CFTR‐RD exhibit minimal pancreatic positive test result should be confirmed by a second test within
function, which leads to PS. Some patients develop pancreatitis, 3 months. Patients with clearly established PEI do not need to un-
which evolves into PEI over time.198,206,207 The prevalence of PEI in dergo further PEI testing. Patients undergoing equivocal exocrine
CP increases with disease duration, ranging 30%–90% of all function tests should be monitored for PS.
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
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Level of evidence: 4; Percentage of agreement: 92.5% pancreatic diseases such as recurrent AP or CP should be given extra
Children with pancreatic sufficiency should be monitored by attention during PEI surveillance testing.199,223 Finally, monitoring
annual FE‐1 or additionally in cases of failure to thrive, weight loss, for signs of exocrine failure (steatorrhea, weight loss, deficiencies in
abdominal pain, or diarrhea. fat‐soluble vitamins, or distal intestinal obstruction syndrome) is
Level of evidence: 4; Percentage of agreement: 92.5% recommended in the follow‐up of all PS patients with CF or CFTR‐
In PS adults (≥16 years age), surveillance for development of PEI RD.215,222
can be individualized according to genotype.

� PS patients with a combination of two classes I‐III known to be What are the clinical consequences of PEI in CF and
associated with intermediate to high prevalence of PEI could be CF‐related disorders?
evaluated with the FE‐1 test annually and additionally if the
development of PEI is suspected. Statement 7.5
� Patients with one or more class IV‐VI mutations, known to be
associated with a low prevalence of PEI, could be evaluated upon The clinical consequences of PEI in CF and CF‐related disorders are
suspected PEI development. comparable to those of other etiologies (Chapter 1). Additionally, PEI
and malnutrition in patients with CF negatively influence growth,
Level of evidence: 4; Percentage of agreement: 92.5% pulmonary function, and survival.
Level of evidence: 1; Percentage of agreement: 96.6%
Comment: Historical studies convincingly highlight that a high‐
Statement 7.4.2 fat, high‐calorie diet and PERT promote the growth and survival of
patients with CF (55). Further studies have confirmed the negative
In patients with CFTR‐RD: effects of poor nutritional status on pulmonary function and
Evaluation of PEI is required as part of the workup for CFTR‐RD survival.224,225
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% How should PERT be performed in patients with CF?
PS patients with CFTR‐RD should be monitored by annual FE‐1
during infancy and childhood or additionally in cases of failure to Statement 7.6.1
thrive, weight loss, deficiencies in fat‐soluble vitamins, and episodes
of AP or diarrhea. PEI treatment in CF follows general recommendations (Chapter 3),
Level of evidence: 4; Percentage of agreement: 92.5% with the particularity that the enzyme dose must be calculated ac-
In PS adults (≥16 years age), surveillance for development of PEI cording to age and body weight.
can be individualized. Level of evidence: 1; Percentage of agreement: 96.2%

� Clinical subtypes with evident recurrent episodes of AP or signs of

CP development should be monitored annually using FE‐1. Statement 7.6.2
� Clinical subtypes with other clinical manifestations (congenital
bilateral absence of the vas deferens or disseminated bronchiec- Patients treated with PERT should be monitored for growth,
tasis) can be evaluated based on the suspected development nutritional status, and abdominal symptoms at regular intervals to
of PEI. determine the adequacy of treatment at every clinic visit for in-
fants and every 3 months for older children, adolescents, and
Level of evidence: 5; Percentage of agreement: 92.5% adults.
Comment: PEI is observed in the majority of patients with CF Level of evidence: 4; Percentage of agreement: 96.2%
and develops with increasing prevalence during the first year of Comment: In clinical practice, administration of enzyme pellets
213–217
life. Patients initially diagnosed with PS early in life have a high to infants can be difficult. If the infant refuses to take the enzyme
risk of declining exocrine function.217–220 The loss of exocrine func- pellets from a spoon with a little expressed breast milk or formula,
tion has implications for the nutritional state and life expectancy of the administration of an acidic puree, such as applesauce, may be
patients with CF.47,213,214,221 The goal of nutritional treatment for successful. If the infant still refuses pellets, the use of unprotected
patients with CF during early life is normal growth and prevention of powdered enzymes may need to be considered temporarily.
nutritional deficiencies. The detection and treatment of exocrine Pancreatic enzymes should not be added to infant feed. For pa-
failure in early life is important for achieving these goals.215,222 For tients of all ages, powdered enzymes can be used to help digest
PS patients with CF and those with CFTR‐RD, the risk of developing enteral tube feedings, for example, when oral administration of
PEI is more difficult to predict. Patients with signs of non‐CF‐specific enzymes is not possible or when jejunostomy feeds are required.
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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Enzymes administered in this situation should not mix with the children aged 2–5 years with homozygous F580del‐CFTR mutations
feed; they should be administered as bolus doses through enteral treated with lumacaftor‐ivacaftor, significant improvements in
feeding tubes. When unprotected powdered enzymes are used, the exocrine pancreatic function (FE‐1 levels and IRT) were noted be-
addition of a PPI may help prevent the inactivation of lipase by tween baseline and 24 weeks of treatment.230 Despite these
gastric acid. For small children, enteric coated pancrelipase enzyme encouraging results, the impact of modulators on PEI in older chil-
preparations have been shown to be safe, effective, and preferred dren is less clear, raising the question of a “window of opportunity”
by parents. for reversing exocrine dysfunction.
Monitoring of growth and nutritional status at regular intervals Thus, these data support the beneficial effects of modulators on
to determine the adequacy of treatment is recommended at each exocrine pancreatic function, especially in young children with CF
monthly clinic visit for infants, every 3 months for children and ad- and those with milder mutations. Nevertheless, further studies are
olescents, and every 6 months for adults. 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.
How should PERT be performed in patients with In patients with PS‐CF and CFTR‐RD, a decline in exocrine func-
CFTR‐RD? tion occurs later in life and may be accelerated by bouts of pancreatitis.
Although data are limited, Ramsey et al. showed that the increased use
Statement 7.7 of modulators (iva, iva þ luma, or teza þ iva) in patients with PS‐CF was
correlated with a 65% relative reduction in hospitalizations for
PERT in patients with CFTR‐RD follows general recommendations pancreatitis.231 These data are further supported by case reports
(Chapter 3). showing that modulators can prevent pancreatitis episodes in patients
Level of evidence: 2; Percentage of agreement: 98.2% 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
How does potentiator/modulator therapy affect PEI in pancreatitis and secondary PEI development.
patients with CF and those with CFTR‐RD? In conclusion, our data suggest that modulators may restore
exocrine function in (young) patients with PEI‐CF, preventing a further
Statement 7.8.1 decline in pancreatic exocrine function in PS‐CF and pancreatitis epi-
sodes in patients with CFTR‐RD and PS‐CF. The impact of modulators
Potentiators and modulators may improve exocrine pancreatic on nutritional support, liposoluble vitamin supplementation, and PERT
function when started early in patients with CFTR‐RD with eligible recommendations requires further investigation.
mutations.
Level of evidence: 3; Percentage of agreement: 98.0%
CHAPTER 8: PEI AFTER PANCREATIC SURGERY

Statement 7.8.2 What is the prevalence of PEI in patients after

pancreatic surgery?
The current data are insufficient to amend the recommendations for
PERT, nutritional requirements, and liposoluble vitamins in patients Statement 8.1
receiving potentiator/modulator therapy.
Level of evidence: 4; Percentage of agreement: 98.0% The prevalence of PEI after pancreatic surgery is highly variable,
Comment: Until the advent of modulation therapy, approxi- ranging from 100% after total pancreatectomy to 10% in some re-
mately 85% of patients with CF were reported to develop PEI by the ports after distal or central pancreatectomies.
age of 1 year. Recent clinical studies using the CFTR‐potentiator Level of evidence: 1; Percentage of agreement: 98.3%
Ivacaftor (ARRIVAL,226 KIWI,227 and KLIMB228) in children aged 1– Comments: The prevalence of PEI after pancreatic surgery varies
5 years support the improvement or recovery of exocrine pancreatic according to the surgical procedure, condition of the pancreas before
function. The ARRIVAL study, studying Ivacaftor in children aged 4 to surgery, tools used to diagnose PEI, and timing of pancreatic function
<12 months229 and 12 to <24 months226 with ≥1 CFTR gating mu- assessment after surgery. The prevalence of PEI is 100% after total
tation, evidenced that levels of FE‐1 and immunoreactive trypsin pancreatectomy, although more than half of patients do not develop
(IRT) improved significantly between baseline and after 24 weeks of PEI‐related symptoms.42,235–237 According to a systematic review,
227 228
treatment. The KIWI and follow‐up KLIMB studies performed the prevalence of PEI after pancreaticoduodenectomy is
in children aged 2–5 years with a CFTR gating mutation showed 92%.59,236,238,239 After distal and central pancreatectomies, the
similar significant improvements in exocrine pancreatic function. In prevalence of PEI is 10%–80%.59,236,238,239
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What is the pathogenesis of PEI after pancreatic What is specific for the treatment of PEI in patients
surgery? after pancreatic surgery?

Statement 8.2 Statement 8.5

The pathogenesis of PEI after pancreatic surgery is multifactorial. PEI treatment after pancreatic surgery follows the general rules
The main contributing factors were the state of the pancreas before described in Chapter 3. However, the initial oral dose of pancreatic
surgery, removal of the pancreatic parenchyma, disruption of the enzymes required in patients after total pancreatectomy and pan-
physiological postprandial stimulation of pancreatic secretion during creaticoduodenectomy may be higher than that generally recom-
duodenal resection, and inadequate mixing of pancreatic enzymes mended for patients with PEI secondary to other conditions.
with nutrients after gastrointestinal reconstruction. Level of evidence: 4; Percentage of agreement: 91.7%
Level of evidence: 1; Percentage of agreement: 98.4%
Comments: The two main factors contributing to the develop-
ment of PEI after pancreaticoduodenectomy are duodenal removal What are the benefits of PERT after pancreatic
and loss of pancreatic parenchyma. The former leads to the disrup- surgery?
tion of autonomic control and inadequate activation of pancreatic
digestive enzymes. The latter leads to an overall reduction in Statement 8.6
pancreatic exocrine secretion.240–242 PEI after distal pancreatectomy
and central pancreatectomy depends on the volume of the remnant The benefits of PERT in patients with PEI after pancreatic surgery are
pancreas,243–247 with a remnant pancreatic volume <39.5% predic- similar to those in patients with other clinical conditions (see Chapter 3).
tive of PEI.247 In addition, direct inactivation of pancreatic enzymes Level of evidence: 2; Percentage of agreement: 98.4%
by gastric acid may be a contributing factor when pancreatogas-
trostomy is performed after pancreaticoduodenectomy or central
pancreatectomy.248,249 How should patients with PEI after pancreatic surgery
be monitored?

How should PEI be diagnosed in patients after Statement 8.7

pancreatic surgery?
Recommendations for the monitoring and follow‐up of patients with PEI
Statement 8.3 after pancreatic surgery follow the general rules described in Chapter 3.
Level of evidence: 5; Percentage of agreement: 98.3%
The diagnosis of PEI in patients after pancreatic surgery mainly fol- Comment: Particularly, after pancreatic surgery, other causes of
lows the general rules described in Chapter 2 with two exceptions. abdominal symptoms should be investigated if the clinical response to
First, no diagnostic confirmation is required after total pancreatec- PERT is inadequate. The differential diagnoses of PEI after surgery
tomy, and second, the FE‐1 test is not suitable for the diagnosis of include superior mesenteric artery revascularization, dissection‐
PEI after pancreaticoduodenectomy. associated diarrhea syndrome, small intestinal bacterial overgrowth,
Level of evidence: 1; Percentage of agreement: 84.2% and dumping syndrome. Similar to other causes of PEI, oncological
Comment: The anatomical and functional consequences of metabolic factors leading to malnutrition, bile acid malabsorption, in-
pancreaticoduodenectomy render the FE‐1 test and the proposed fectious diarrhea (e.g., Clostridium difficile), lactase deficiency, food
cut‐off values inadequate for the diagnosis of PEI. Therefore, a intolerance, CeD, IBD, IBS, and diabetic diarrhea should be considered
universally accepted approach for diagnosing PEI after pancreatic in patients with an inadequate clinical response to PERT.
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 CHAPTER 9: PEI AFTER UPPER GASTROINTESTINAL
(ESOPHAGEAL, GASTRIC, AND BARIATRIC)
SURGERIES
What are the clinical consequences of PEI after
pancreatic surgery? What is the prevalence of PEI in patients who have
undergone upper GI surgery?
Statement 8.4
Statement 9.1
The clinical consequences of PEI after pancreatic surgery are similar
to those of other clinical conditions (see Chapter 1). The prevalence of PEI after upper gastrointestinal surgery is 9%–67%,
Level of evidence: 2; Percentage of agreement: 98.4% depending on the type of surgery and the test used to diagnose PEI.
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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Level of evidence: 3; Percentage of agreement: 96.9% Statement 9.3.2

Comment: Three prospective cohort studies measured
exocrine pancreatic function after esophagectomy and found PEI in Although not specific to PEI, symptoms of maldigestion and nutri-
16%–57% of patients.252–255 Clinical data on the prevalence of PEI tional deficiencies can be used to suspect PEI in patients who have
after gastric surgery are limited to small studies.256–258 A study undergone upper gastrointestinal surgery.
using pancreatic stimulation with intravenous secretin and cerulein Level of evidence: 5; Percentage of agreement: 84.6%
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 Statement 9.3.3
measured by the secretin‐cerulein test, within 3 months of sur-
gery.256 Subtotal gastrectomy leads to altered fat digestion and The 13C‐MTG breath test and quantification of the CFA could be
absorption in about two‐thirds of patients, particularly after Roux‐ used to diagnose PEI after upper gastrointestinal surgery.
en‐Y reconstruction compared with Billroth I reconstruction.257 Level of evidence: 5; Percentage of agreement: 91.8%
Based on a small number of studies, the prevalence of PEI after Comment: PEI after upper gastrointestinal surgery cannot be
259–261
bariatric surgery is 9%–48%. In a study using FE‐1, 48% of diagnosed using the same methodology as that in patients with normal
the patients after distal Roux‐en‐Y gastric bypass (RYGB) and 19% gastrointestinal anatomy (see Chapter 2). FE‐1 allows the assessment
after proximal RYGB showed reduced pancreatic secretion.259 In of pancreatic secretion but does not measure the effect of postprandial
another study, low pancreatic secretions were found in 10.3% and asynchrony between gastric emptying of chyme and pancreatic
260
4.2% of the patients after RYGB and gastric sleeve, respectively. secretion during food digestion. In contrast to FE‐1, the 13C‐MTG
Using the 13C‐MTG breath test, the prevalence of PEI in patients breath test and fecal fat quantification assess the digestion and ab-
after bariatric surgery ranges from 4.3% after general surgery and sorption of fat, and can therefore be used to diagnose PEI after upper
8.3% after RYGB to 75% after biliopancreatic diversion with GI surgery.43
duodenal switch (22).

What are the clinical consequences of PEI in patients

What is the specific pathogenesis of PEI in patients who undergo upper gastrointestinal surgery?
who undergo upper gastrointestinal surgery?
Statement 9.4
Statement 9.2
The clinical consequences of PEI in patients after upper gastroin-
PEI after upper gastrointestinal surgery may be the result of impaired testinal surgery may be similar to those of other causes PEI (see
stimulation of digestive enzyme secretion (humoral and neural) and Chapter 1).
postprandial gastrointestinal asynchrony. Level of evidence: 3; Percentage of agreement: 93.9%
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 What is the treatment of PEI in patients who undergo
postprandial stimulation of pancreatic secretion and asynchrony upper gastrointestinal surgery?
between the gastric emptying of nutrients and biliopancreatic
secretion.43 Therefore, the accuracy of quantifying pancreatic Statement 9.5
secretion using FE‐1 testing for the diagnosis of PEI in these condi-
tions was lower than that in patients with normal gastrointestinal PEI treatment after upper gastrointestinal surgery follows general
anatomy. recommendations (see Chapter 3).
Level of evidence: 5; Percentage of agreement: 96.9%
Comment: There is little evidence on whether PERT capsules
How can PEI be diagnosed in patients who underwent should be opened and the pellets swallowed with acidic liquid or
upper gastrointestinal surgery? semi‐solid food (pH < 5.5) after gastrectomy to allow their better
mixing with food.262 PERT has been suggested to prevent post-
Statement 9.3.1 operative maldigestion and weight loss.256 After bariatric surgery,
appropriate PERT should be considered part of the management al-
FE‐1 is not a reliable test for PEI after upper gastrointestinal gorithm for patients with confirmed PEI and symptoms or nutritional
surgery. deficiencies suggestive of this complication.263 However, the role of
Level of evidence: 5; Percentage of agreement: 83.6% PERT in these patients is unclear because there is insufficient
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
24
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evidence to determine whether or to what extent, this therapy in- tests, and FE‐1 levels in individuals with DM emphasize the need to
terferes with the goals of bariatric surgery.259 consider alternative causes of steatorrhea such as CeD and bacterial
overgrowth in the small intestine.268

CHAPTER 10: PEI AND DIABETES MELLITUS (DM)

Should patients with DM be screened for PEI?
What is the prevalence of PEI in patients with DM?
Statement 10.4
Statement 10.1
Patients with types 1 and 2 DM should only be screened for symp-
Reduced pancreatic secretion, as assessed by FE‐1 levels, is toms or nutritional deficiencies consistent with PEI.
common in patients with type 1 and type 2 DM. The prevalence Level of evidence: 3; Percentage of agreement: 94.2%
of PEI, according to the agreed‐upon definition (Chapter 1) is Comment: Although reduced pancreatic secretions may be com-
unknown. mon in patients with DM, general screening is not recommended.
Level of evidence: 3; Percentage of agreement: 94.2% However, symptoms consistent with PEI should be carefully assessed.
Comment: Reduced pancreatic secretion, defined by low FE‐1, If type 3c (pancreatogenic) DM is suspected, exocrine pancreatic
is consistently more common in people with DM than in controls, function should be assessed.
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 What are the specific clinical consequences of PEI in
strictly excluded pancreatogenic diabetes reported a prevalence patients with DM?
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 Statement 10.5
268–270
and may correlate with DM duration, but this is still
debated. 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 un-
What is the pathogenesis of PEI in patients with DM? derlying pancreatic diseases to ensure early diagnosis and
treatment.
Statement 10.2 Level of evidence: 5; Percentage of agreement: 98.6%
Comment: Both pancreatitis and pancreatic malignancies are
The pathogenesis of PEI in patients with DM is multifactorial, com- associated with PEI. As patients with DM are at an increased risk of
plex, and incompletely understood. both conditions, the development of PEI may require further inves-
Level of evidence: 4; Percentage of agreement: 97.1% tigation in suspected cases.
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 dysfunc- What is the specific treatment of PEI in patients
tion,271,272 fibrosis, pancreatic steatosis, and dysregulation of other with DM?
islet hormones such as glucagon and somatostatin.271
Statement 10.6

How can PEI be diagnosed in patients with DM? PEI treatment in patients with DM patients follows general recom-
mendations (Chapter 3).
Statement 10.3 Level of evidence: 5; Percentage of agreement: 97.2%

The diagnosis of PEI in patients with DM follows general recom-

mendations (Chapter 2). What are the specific benefits of PERT in patients
Level of evidence: 1; Percentage of agreement: 100% with DM?
Comment: PEI symptoms are usually mild in patients with DM.
Typical abdominal discomfort, diarrhea, and flatulence may be mis- Statement 10.7
interpreted as drug‐related (metformin and glucagon‐like peptide‐1
agonists) or secondary to diabetic neuropathy. Studies showing In addition to the general benefits of PERT mentioned in Chapter 3,
weak correlations between fecal fat excretion, pancreatic function glucose homeostasis may also be positively influenced by PERT;
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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however, the evidence is conflicting. Treatment with PEI may levels were reported in 21.7% of participants aged >60 years.288
improve cardiovascular risk in patients with DM. Although the clinical relevance of PEI in aging is unknown, older in-
Level of evidence: 5; Percentage of agreement: 86.2% dividuals with proven PEI should not be treated differently from other
Comment: PEI is associated with an increased cardiovascular patients with this condition.
risk.273 Therefore, its treatment may be particularly beneficial for
patients with DM who are at a high risk of cardiovascular disease.
What is the prevalence and clinical relevance of PEI in
non‐alcoholic fatty pancreas disease?
How should patients with DM and PEI be monitored?
Statement 11.2
Statement 10.8
The clinical relevance of fatty pancreas and whether it can cause PEI
Monitoring of patients with DM and PEI follows general recom- remain unclear.
mendations (Chapter 3). Level of evidence: 4; Percentage of agreement: 95.3%
Level of evidence: 3; Percentage of agreement: 98.6% Comment: A systematic review of five studies on fatty pancreas
Comment: Special attention should be paid to the diagnosis and showed PEI in 9%–56% of patients.289 Among 31 patients with MRI
treatment of osteoporosis as it is a common complication of both signs of pancreatic steatosis and 25 controls, FE‐1 levels were lower in
conditions.72,274 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
What is the relation between PEI and type 3c and PEI.291 In contrast, an inverse relationship between the amount of
(pancreatogenic) DM? pancreatic fatty accumulation on MRI and FE‐1 levels was reported in a
large population‐based study.292 Fatty pancreas is particularly com-
Statement 10.9 mon 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
Both PEI and type 3c DM result from the same pancreatic injury, normal, and symptoms of PEI and nutritional deficiencies are
most commonly CP, PC, or previous pancreatic surgery, and less lacking.289
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 What is the prevalence and clinical relevance of PEI in
obvious cause of type 3c DM, but it accounts for only 2% of cases.275 hemochromatosis?

Statement 11.3
CHAPTER 11: PEI IN OTHER CONDITIONS
The prevalence and clinical relevance of PEI in hemochromatosis is
What is the prevalence and clinical relevance of PEI in not known.
aging? Level of evidence: 5; Percentage of agreement: 98.4%
Comment: Data on the association between hemochromatosis
Statement 11.1 and PEI are lacking. Two small studies were published decades
ago293,294 and a few case reports were published thereafter.295,296
Exocrine pancreatic function may be impaired with aging. Low FE‐1 All other available data came from studies performed on patients
levels have been reported in 21.7% of patients aged >60 years and with other iron overload disorders such as beta‐thalassemia ma-
11.5% of people aged 50–75 years. jor.297–299 The studies were heterogeneous and used different
Level of evidence: 4; Percentage of agreement: 93.9% methods to diagnose PEI, making the results difficult to interpret.
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 What is the prevalence and clinical relevance of PEI in
as a risk factor for PEI,277–279 other reports support this claim.280–288 celiac disease?
In the old age, significantly lower enzyme and/or bicarbonate output
following the secretin test has been reported281–285 and confirmed Statement 11.4
using FE‐1 as an indicator of exocrine secretion.287,288 The largest
study conducted so far in a population‐based cohort of 914 partici- Low FE‐1 levels and pathological BT‐PABA test have been reported
pants aged 50–75 years showed low FE‐1 levels (<200 μg/g) in 11.5% in 10.5%–46.5% of new patients with CeD (pooled prevalence
of the study participants.287 In another study of 159 patients, low FE‐1 26.2%). PEI testing should be considered if significant malnutrition is
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26
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present at the diagnosis of CeD or if there are persisting symptoms Level of evidence: 4; Percentage of agreement: 88.1%
that do not respond to a gluten‐free diet (GFD). Comment: FE‐1 <200 μg/g and <100 μg/g have been reported in
Level of evidence: 4; Percentage of agreement: 97.1% 7.1%–13.3% and 4.4%–6% of patients with D‐IBS, respectively.314–317
Comment: The mechanism of PEI in newly diagnosed CeD is A recent systematic review and meta‐analysis evaluated the preva-
likely reduced CCK and secretin release, with intrinsically normal lence of somatic conditions in patients with IBS318 and reported a
pancreatic morphology and function.300–302 A systematic review and crude pooled prevalence of PEI of 4.6%. Investigations of the pancreas
meta‐analysis reported a pooled prevalence of PEI (based on FE‐1 or using imaging have not been uniform or systematic in most studies.
BT‐PABA test) of 26.2% (range, 10.5%–46.5%) in patients with newly Underlying pancreatic abnormalities, including pancreatic atrophy,
diagnosed CeD versus 8% in those on a GFD.303 In a Swedish fatty pancreas, and CP, have been found in patients with IBS.314,317,319
nationwide study, patients with CeD had a 5.34‐fold increased risk of In the absence of any underlying pancreatic disease, false‐positive FE‐1
receiving pancreatic enzyme product supplementation after CeD results cannot be excluded in patients with D‐IBS, and comparisons
diagnosis.304 A double‐blind prospective study including 40 children with other exocrine pancreatic function tests have not been reported.
(mean age: 14.3 months) showed a limited benefit of PERT at diag- Treatment with PERT is not well‐documented in this setting, and no
nosis (an increased weight gain for patients taking PERT was randomized or blinded studies have been conducted. Symptomatic
305
detected in the first 30 days but not thereafter). Although improvement in patients with IBS on PERT has been described in small
pancreatic function tests are not routinely recommended for patients open studies.314 A double‐blind randomized controlled trial found no
with newly diagnosed CeD, testing with FE‐1 and PERT may be benefit from PERT in D‐IBS; however, pancreatic function was not
considered for patients with significant malnutrition. Reassessment evaluated.320 Other studies have described some patients reporting
should be recommended after 30 days according to Italian guide- benefits from PERT; however, these studies were of low quality with a
lines.14 Other international guidelines recommend testing FE‐1 in high placebo effect.321,322
306,307
patients with CeD with a partial response to a GFD.

What is the prevalence and clinical relevance of drug‐

What is the prevalence and clinical relevance of PEI related PEI?
in IBD?
Statement 11.7
Statement 11.5
Low FE‐1 values have been reported in 1%–10% of patients treated
Low FE‐1 values have been reported in 0%–41% of patients with IBD with immune‐checkpoint inhibitors and tyrosine kinase inhibitors.
and in 19%–31% of patients with AIP and IBD. Level of evidence: 4; Percentage of agreement: 95.2%
Level of evidence: 4; Percentage of agreement: 93.9% Comment: Pancreatic atrophy has been reported in 7.7% of
Comment: A Reduced pancreatic secretion based on the patients with cancer treated with immune‐checkpoint inhibitors, and
secretin‐cerulein test was reported in 41% of patients with IBD.308 1.1% developed PEI that resolved with PERT.323 A low FE‐1 level
Low FE‐1 levels have been reported in 18% of patients with IBD, was reported in 10% of patients with hepatocellular carcinoma
which was associated with more than three bowel movements per (HCC) treated with sorafenib, and malabsorption symptoms in these
309
day, loose stools, and previous gastrointestinal surgery, and in patients resolved with PERT.324 Similarly, steatorrhea that resolved
310
10% of patients according to a systematic review. In contrast, with PERT has been described in 35% of patients with HCC or renal
FE‐1 was normal in 20 patients with Crohn's disease, most of cell carcinoma treated with sorafenib in a study that also reported
them with FE‐1 values > 500 μg/g, which strongly indicated the vitamin D deficiency, hypophosphatemia, and secondary hyperpara-
311
absence of PEI. In patients with IBD and AIP, low FE‐1 values thyroidism in these patients.325 Significant pancreatic atrophy, but
312 313
were reported in 19% and 31% of patients, respectively. not PEI, has been described in patients with gastrointestinal stromal
However, the clinical relevance of PEI in patients with IBD remains tumor treated with sunitinib compared with controls,326 and
unclear. pancreatic volume was found to be significantly reduced in patients
with colorectal cancer after bevacizumab therapy, but none devel-
oped PEI.327
What is the prevalence and clinical relevance of PEI in
patients fulfilling the criteria of IBS?
What is the prevalence of PEI in rare/inherited
Statement 11.6 disease?

There is symptomatic crossover between diarrhea‐predominant ir- Statement 11.8

ritable bowel syndrome (IBS‐D) and PEI. Low FE‐1 values have been
reported in 4%–13% of patients with D‐IBS. Whether PEI coexists PEI can occur in patients with Shwachman‐Bodian‐Diamond syndrome
with IBS or causes symptoms suggestive of IBS remains unclear. (SBDS), Johanson‐Blizzard syndrome (JBS), Pearson syndrome,
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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Shteyer syndrome, or other rare inherited diseases. The prevalence of Level of evidence: 4; Percentage of agreement: 98.5%
PEI in these inherited diseases is unknown because of their rarity. Comment: Reduced exocrine pancreatic function is rarely
Level of evidence: 4; Percentage of agreement: 98.4% observed in patients with biliary or hepatic disease.347 A retro-
Comment: After CF (see Chapter 7), SBDS is the second most spective analysis of 37 patients (10 children and 27 adults)
common inherited cause of PEI, with an estimated incidence of who underwent endoscopic retrograde cholangiopancreatography
1:50,000.328 PEI improves with age in these patients. While 90% of for choledochal cysts revealed no evidence of PEI.348 In
infants and young children experience steatorrhea, approximately a study of 40 children with extrahepatic and intrahepatic chole-
half of patients in their second decade of life have a sufficient stasis, FE‐1 levels were within the normal range.349 Normal
329
pancreas and no longer require PERT. exocrine pancreatic function was demonstrated by the secretin‐
JBS is a peculiar nasal malformation with hypo‐ or aplasia of the pancreozymin test in five patients with Wilson's disease,
nasal wings and oligodontia of the permanent teeth and presents as either without or with cirrhosis, but without portal
congenital PEI.330 The onset of PEI in patients with JBS may be hypertension.350
delayed until adolescence.331
PEI has been reported in patients with Pearson syndrome,332
Shteyer syndrome,333 complete or incomplete pancreatic agen- What is the prevalence of PEI in chronic renal failure/
esis,334,335 heterozygous HNF1B mutations,336,337 isolated inherited chronic uremia?
deficiencies of pancreatic digestive enzymes or duodenal enter-
opeptidase (enterokinase),338 and mutations in chymotrypsin‐like Statement 11.11
elastase (CELA) gene. Additionally, mutations in the carboxyl ester
lipase (CEL) gene have been reported to cause diabetes and pancre- The prevalence of PEI in chronic kidney disease (CKD) has been re-
atic exocrine dysfunction.339 ported in up to 72% of patients. However, these studies are of low
quality.
Level of evidence: 4; Percentage of agreement: 92.3%
What is the prevalence of PEI in infectious diseases? Comment: Pancreatic secretion, as assessed using the secretin‐
pancreozymin test, was found to be abnormal in 72% of patients
Statement 11.9 with CKD.351 Another study using the same test showed significantly
reduced amylase secretion, total secretory volume, and bicarbonate
Low FE‐1 levels have been reported in 20%–50% of patients with secretion in patients with CKD.352 There are no specific data on the
HIV. PEI is possible in other infectious diseases, but its prevalence PEI and PERT in these patients.
remains unknown.
Level of evidence: 4; Percentage of agreement: 93.8%
Comment: Symptomatic PEI has been documented in 20%–50% What is the prevalence of PEI in patients under
of patients with chronic HIV infection.340–343 There are many studies somatostatin treatment?
in the literature indicating an association between bacterial patho-
gens and AP.344 However, the existing literature is usually of low Statement 11.12
quality and ancient. Tuberculosis has been described in the first pa-
tient ever treated with pancreatic extracts for PEI; however, the rate The prevalence of PEI varies from 8% to 24% in patients treated with
of PEI is unknown.345 Parasites with reported AP associations include somatostatin analogs (SSAs).
Ascaris lumbricoides, Fasciola hepatica, and Echinococcus gran- Level of evidence: 4; Percentage of agreement: 98.5%
344
ulosus. One of the largest studies in an Indian endemic area found Comment: SSAs significantly inhibit pancreatic enzyme secretion
ascariasis in 23% of patients with AP; however, no data on PEI are and suppress the release of hormones, including secretin, CCK, and
available.346 motilin.353–356 In a study of patients treated with lanreotide alone or
in combination with interferon alpha, steatorrhea was present in 8%
of patients treated with lanreotide alone but in none of those treated
What is the prevalence of PEI in chronic liver/biliary with combined therapy.357 Pancreatic secretion, as assessed by the
diseases? FE‐1 test, was slightly reduced in 20% of patients with non‐
pancreatic neuroendocrine tumors (NETs) treated with SSAs for at
Statement 11.10 least 1 year, with no patients having an FE‐1 <100 μg/g.358 In
another study involving 50 patients with well‐differentiated NET,
There is no strong evidence for PEI in patients with chronic hep- PEI was reported in 12 (24%) patients at a median of 2.9 months
atobiliary diseases other than excessive alcohol consumption (see after initiation of SSAs.359 The quantitative fecal fat test was
statement 11.2 for PEI in non‐alcoholic fatty liver disease and non‐ abnormal in 17% of patients with NET on SSA therapy, with a median
alcoholic fatty pancreas disease). time to PEI of 12 months.360
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What is the prevalence of PEI in patients with none of the controls.366 In a similar study, 63% of the patients were
pancreatic tumors other than PC? reported to have abnormal pancreatic function.367 Pancreatic
dysfunction has been found in 25%–33% of patients with SS using
Statement 11.13 sMRCP and the Lundh test.368 Finally, pancreatic function, as eval-
uated by FE‐1 and 13C‐MTG breath tests, was reported as normal in
The prevalence of PEI in patients with pancreatic neoplasms other than 57 patients with primary SS.369
ductal adenocarcinoma remains unknown. Most studies on these pa-
tients reported postoperative PEI. Patients with pancreatic NETs may
develop PEI, which may be due to long‐term treatment with SSAs. DISCUSSION
Level of evidence: 4; Percentage of agreement: 92.5%
Comment: Most available studies on PEI in patients with PNETs The first relevant consensus reached in this document is the defini-
present data on pancreatic function and nutritional status in patients tion of PEI as a reduction in exocrine pancreatic secretion to the level
treated with SSAs (see Statement 11.12) or after tumor resection (see that prevents normal digestion of nutrients. This has important
Chapter 8). In a retrospective study of 82 patients (von Hippel‐Lindau, clinical implications as the threshold for PEI can be influenced by
n = 25; multiple endocrine neoplasia type I, n = 20; sporadic, n = 37) several factors; therefore, reduced pancreatic secretion should not
who underwent resection of PNETs, none had a recorded pre‐ be considered synonymous with PEI. It is generally accepted that a
operative PEI.361 In a prospective study using the FE‐1 test, pancre- reduction in pancreatic secretion of more than 90% of normal is
atic secretion was reduced in 24% of patients with well‐differentiated required for maldigestion to develop.1 The common clinical scenario
NET.359 However, in another study, FE‐1 levels in patients with gas- of pancreatic secretion that is reduced but sufficient for normal
troenteropancreatic NET tended to be lower but were not significantly nutrient digestion cannot be defined as PEI but as exocrine pancre-
different in patients with or without SSA therapy.362 atic dysfunction. This concept should be considered in the diagnosis
of PEI in clinical practice and future clinical trials.
The second important consequence of this definition is that it
What is the prevalence of PEI in patients with chronic challenges existing scientific evidence on PEI. Many clinical studies
heart failure (CHF)? on PEI have used abnormal results in pancreatic secretion tests such
as FE‐1 as criteria for defining PEI. Consequently, patients with
Statement 11.14 pancreatic dysfunction are often mistakenly diagnosed as having PEI,
leading to biased results.
Low levels of FE‐1 have been reported in 6.9%–56.7% of patients Because tests to assess nutrient digestion are either cumbersome
with CHF. (e.g., CFA) or of limited availability (e.g., 13C‐MTG breath test), this
Level of evidence: 4; Percentage of agreement: 88.9% guideline proposes, as a general rule, the global assessment of PEI‐
Comment: Reduced splanchnic blood flow may affect pancreatic related symptoms, nutritional status, and pancreatic secretion to di-
function in patients with CHF. Pancreatic secretion, as assessed using agnose PEI in an appropriate clinical scenario until simple and accurate
the FE‐1 test, was abnormally low in 6.9% of patients with CHF.363 In digestion tests are widely available. Different likelihoods of PEI in
addition, FE‐1 levels were significantly lower in patients with CHF different clinical conditions significantly influence the diagnostic
364
than in controls. In another study, PEI was reported in 56.7% of approach for PEI in clinical practice. The specificities of PEI‐based
patients with CHF and in none of the patients with normal heart diagnosis for different diseases are presented in this document.
function.365 In this study, patients with PEI were randomized to Due to the malabsorption of nutrients, abdominal and bowel
receive PERT or a placebo, and PERT was associated with a signifi- symptoms and nutritional deficiencies are among the consequences
cant improvement in appetite loss.365 of PEI that affect patients' QoL and are associated with long‐term
malnutrition‐related complications.27,45–47,62,66,86–89,156,190,270
Therefore, PEI always requires treatment, and relief of symptoms and
What is the prevalence of PEI in patients with normalization of nutritional status are the therapeutic goals. Other
Sjögren's syndrome? clinical consequences of PEI are disease‐specific and are described in
this document.
Statement 11.15 Generally, the PEI treatment is based on nutritional advice and
support and PERT. The PERT dose should be individualized and is
The prevalence of PEI in patients with Sjögren's syndrome (SS) varies likely to be influenced by the severity of PEI and dietary habits
widely, ranging 0%–63%, depending on the method used for PEI (amount, calories, and fat content of food). Although a starting dose
diagnosis. However, the quality of the evidence is low. of 40,000–50,000 units with main meals and half of this dose with
Level of evidence: 4; Percentage of agreement: 92.1% snacks is generally recommended for adult patients,24 this dose may
Comment: Pancreatic function based on the BT‐PABA test was be insufficient in patients with severe PEI, such as those with PC and
found to be abnormal in 37.5% of patients with SS compared with those who have undergone pancreatoduodenectomy or total
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
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pancreatectomy.182,248 Acidic intraluminal gut pH is a known factor CONCLUSION

that influences the efficacy of PERT, and the addition of PPI to PERT
may be required.121,122 The specificities of the PEI therapy for The definition, pathogenesis, clinical consequences, diagnosis, treat-
different diseases are outlined in this document. ment, and monitoring of PEI in different clinical conditions have been
Unmet needs and future directions (Figure 2) systematically reviewed, and a consensus has been reached regarding
The unmet needs identified in each chapter were derived from a these multidisciplinary, evidence‐based European clinical guidelines. It
review of relevant scientific evidence, and were proposed by each also highlights the unmet needs and areas where scientific evidence is
WG. They were then endorsed by consensus. weak or lacking to guide future research. PEI is associated with mal-
Despite the large number of published studies, the scientific digestion and malabsorption of nutrients, resulting in intestinal
evidence on PEI is rather weak. The change in the concept of PEI, as a malabsorption and nutritional deficiencies that negatively affect the
reduction in pancreatic secretion severe enough to affect the patients' QoL and are associated with long‐term malnutrition‐related
digestion of nutrients, means that a relevant proportion of previously complications and mortality. Along with appropriate management of
published studies no longer fit the new concept. the underlying conditions causing PEI, knowledge of when and how to
Considering the concept of PEI reported in these guidelines, the diagnose PEI, optimal therapy and therapeutic goals, and appropriate
actual prevalence of PEI in various pancreatic diseases, pancreatic monitoring of patients are essential to reduce the risk of complications
and gastrointestinal surgeries, and other clinical conditions remains and improve the QoL and survival of patients with PEI.
largely unknown. Most studies rely on the results of the FE‐1 test,
which reflects the secretion but not the digestive capacity of the A C K NO W L E DG M E NT S
pancreas. Although the FE‐1 test is sensitive for diagnosing PEI, its The authors thank the following member societies of the United
specificity is not higher than expected. The prevalence of PEI may European Gastroenterology (UEG) for participating in and endorsing
have been overestimated in different clinical scenarios. Therefore, these guidelines: European Digestive Surgery (EDS), European Soci-
there is a need for new epidemiological studies that include patients ety for Primary Care Gastroenterology (ESCPG), European Society
diagnosed with PEI based on the current recommendations. for Pediatric Gastroenterology, Hepatology and Nutrition
Therefore, the development of a test or biomarker for diagnosing (ESPGHAN), European Society for Clinical Nutrition and Metabolism
PEI is urgently required. The CFA remains the reference method for (ESPEN), European Society of Digestive Oncology (ESDO), and Eu-
PEI diagnosis. However, this test is cumbersome, unpleasant, and ropean Society of Primary Care Gastroenterology (ESPCG). We
difficult to comply with. The 13C‐MTG breath test is a promising thank the UEG for the unrestricted educational grant, which enabled
alternative to CFA, but is currently only available in a limited number of the independent conduct of these guidelines. The authors are
76 indebted to Dawn Swibold, general manager at the EPC, for assisting
countries, and standardization is still required. Therefore, research
on new biomarkers for the diagnosis of PEI should be encouraged. in the development of these guidelines. The authors would like to
The treatment of PEI is another area where there are still many express their gratitude to Jin Lee (President of the Korean Pan-
unmet needs. Except for the clinical trials that included patients creatobiliary Association, Hallym University Dongtan Sacred Heart
based on CFA, most other therapeutic trials on PERT are biased by Hospital, South Korea), Kyoichi Takaori (Kyoto University, Dept. of
the inappropriate inclusion of patients. In contrast, the requirement Surgery, Division of Hepatobiliary‐Pancreatic Surgery and Trans-
of using CFA as the main outcome to evaluate the efficacy of PERT in plantation, Japan), and Oscar Mazza (Department of Surgery, Hos-
patients with PEI significantly limits the inclusion of patients in pital Italiano, Buenos Aires, Argentina) for their invaluable
clinical trials. In this context, the 13C‐MTG breath test is much contributions as an independent group of experts. The authors would
simpler and probably as effective as CFA76,77; however, it has not yet like to thank the patient organizations PC Europe (PCE), PALEMA
been approved by drug authorities. Other outcomes such as symp- (Sweden), and the German “Arbeitskreis der Pankreatektomierten”
tom relief, QoL using patient‐reported outcome instruments, and (AdP) for their invaluable contributions to the development of these
nutritional improvement are clinically relevant. guidelines. The following colleagues contributed as WG members and
Most of the available evidence on PERT is based on enzyme as members of the European PEI Multidisciplinary Group are co‐
preparations containing small enteric‐coated pellets of porcine authors of these guidelines: Hana Algül: Comprehensive Cancer
origin.27,39,84,193 Other preparations, including those commercially Center Munich TUM, Institute for Tumor Metabolism, Technical
available in certain countries, have been evaluated to a lesser extent. University of Munich, Munich, Germany. Livia Archibugi: Pan-
Furthermore, owing to the limited production capacity of porcine creatobiliary Endoscopy and Endosonography Division, Pancreas
enzymes, new enzyme preparations from other sources are urgently Translational & Clinical Research Center, IRCCS San Raffaele Scien-
needed. tific Institute, Milan, Italy; Vita‐Salute San Raffaele University, Milan,
The optimal and most effective enzyme dose for different dis- Italy. Marianna Arvanitakis: Service de Gastroenterologie, d’Hepato‐
eases and clinical conditions, the relationship between the enzyme Pancreatologie et d’Oncologie digestive, Hopital Erasme, HUB,
dose and clinical effect, and the importance of modifying the intra- Bruxelles, Belgium. Sorin Barbu, Ovidiu Fabian: 4th Surgery
luminal pH on the efficacy of PERT are areas where more robust Department, University of Medicine and Pharmacy “Iuliu Hatieganu”
evidence is needed. Cluj‐Napoca, Romania. Georg Beyer, Julia Mayerle: Department of
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
30
- UNITED EUROPEAN GASTROENTEROLOGY JOURNAL

Medicine II, Ludwig Maximilian University Hospital, Munich, Ger- Romania. Sophie Gohy: Department of Pneumology, Cliniques Uni-
many. Mihailo Bezmarevic: Department of Hepatobiliary and versitaires Saint‐Luc, Université Catholique de Louvain, Brussels,
Pancreatic Surgery, Clinic for General Surgery, Military Medical Belgium; Cystic Fibrosis Reference Center, Cliniques Universitaires
Academy, University of Defense, Belgrade, Serbia. Frank Bodewes: Saint‐Luc, Université Catholique de Louvai, Brussels, Belgium. Philip
Division of Pediatric Gastroenterology/Hepatology, Beatrix Chil- Hardt: Institute for Endocrinology, Diabetology, and Metabolism,
dren's Hospital/University Medical Center Groningen, University of Johannes Wesling University Hospital Minden, Minden, Germany;
Groningen, Groningen, Netherlands Marja A. Boermeester: Amster- Justus‐Liebig University Giessen, Giessen, Germany. Truls Hauge:
dam UMC Location University of Amsterdam, Department of Sur- Department of Gastroenterology, Oslo University Hospital, Ullevål,
gery, Meibergdreef 9, Amsterdam, The Netherlands; Amsterdam Norway; University of Oslo, Clinical Medicine, Oslo, Norway. Andrew
Gastroenterology, Endocrinology & Metabolism, Amsterdam, Hopper: Department of Infection, Immunity and Cardiovascular
Netherlands Dmitry Bordin: Department of Upper Gastrointestinal, Disease, University of Sheffield, Sheffield, United Kingdom. Julio
Pancreatic, and Biliary Diseases, A.S. Loginov Moscow Clinical Iglesias‐Garcia: Department of Gastroenterology and Hepatology,
Research Center, Moscow, Russia; Department of Outpatient Ther- University Hospital of Santiago de Compostela, Spain. Jutta Keller:
apy and Family Medicine, Tver State Medical University, Tver, Russia. Department of Internal Medicine, Israelitic Hospital, Hamburg, Ger-
Marco Bruno: Department of Gastroenterology & Hepatology, many. Mariia Kiriukova: Pancreatic, Biliary, and Upper GI Diseases
Erasmus University Medical Center, Rotterdam, The Netherlands Department, Moscow Clinical Scientific Center, Moscow, Russia. Jörg
Güralp Ceyhan: Department of General Surgery, HBP‐Unit, School of Kleeff: Department of Surgery, Martin‐Luther‐University Halle‐
Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Wittenberg, 06120 Halle (Saale), Germany. Alexander Kleger: Insti-
Istanbul, Turkey. Laszlo Czako: Center for Gastroenterology, Uni- tute of Molecular Oncology and Stem Cell Biology (IMOS), Ulm
versity of Szeged, Szeged, Hungary. Ferdinando D'Amico: IRCCS San University Hospital, 89081, Ulm, Germany; Division of Interdisci-
Raffaele Hospital, Department of Gastroenterology and Endoscopy, plinary Pancreatology, Department of Internal Medicine I, Ulm Uni-
Milan, Italy. Enrique De Madaria: Department of Gastroenterology, versity Hospital, 89081, Ulm, Germany. Andrea Laghi: Radiology
Dr. Balmis General University Hospital‐ISABIAL, Alicante, Spain. Unit, Department of Medical Surgical Sciences and Translational
Julian De Martino, Sebastien Gaujoux: Department of Hepato‐Biliary, Medicine, “Sapienza” Univeresity of Rome, Sant’Andrea University
Pancreatic Surgery and Liver Transplantation, Hôpital la Pitié‐Sal- Hospital, Via Di Grottarossa, 1035–1039, 00189, Rome, Italy. José
pêtrière, AP‐HP, Paris, France; Sorbonne Université, Paris, France. Larino‐Noia: Hospital Clinico Universitario de Santiago de Compos-
Pierre H. Deprez: Department of Gastroenterology and Hepatology, tela, Santiago de Compostela, Spain. Johanna Laukkarinen: Depart-
Cliniques Universitaires Saint‐Luc, Université Catholique de Louvain, ment of Gastroenterology and Alimentary Tract Surgery, Tampere
Brussels, Belgium. Christos Dervenis: Department of Surgery, AGIA University Hospital, Finland; Tampere University, Faculty of Medicine
OLGA Hospital, Athens, Greece. Petr Dité: Internal Gastroenterology and Health Technology, Tampere, Finland. John Leeds: HPB Unit and
Clinic, University Hospital Brno; Brno; Faculty of Medicine, Univer- Department of Gastroenterology, Newcastle upon Tyne Hospitals
sity of Ostrava, Ostrava, Czech Republic. Asbjørn Drewes: Mech‐ NHS Foundation Trust, United Kingdom; Population Health Sciences
Sense, Department of Gastroenterology and Hepatology, Aalborg Institute, Newcastle University, United Kingdom. Björn Lindkvist:
University Hospital, Aalborg, Denmark. Sinead N. Duggan: Center for Department of Medicine, Sahlgrenska University Hospital, Gothen-
Public Health, Institute of Clinical Sciences, Queen's University Bel- burg, Sweden. Etna Masip: Hospital Universitari i Politecnic La Fe,
fast, Northern Ireland. Deniz Duman: Department of Gastroenter- Valencia, Spain. Giovanni Marchegiani: Department of Surgical,
ology, School of Medicine, Marmara University, Istanbul, Turkey. Oncological, and Gastroenterological Sciences, University of Padua,
Trond Engjom: Department of Gastroenterology, Haukeland Uni- Padua, Italy. Amir Maril: Gastroenterology Institute and Neuro-
versity Hospital, Bergen, Norway. Nils Ewald: Institute for Endocri- gastroenterology Unit, Nazareth Hospital, Nazareth, Israel; Bar Ilan
nology, Diabetology and Metabolism, Johannes Wesling University Faculty of Medicine, Nazareth, Israel. Emma Martinez‐Moneo:
Hospital Minden, Minden, Germany. Nils Ewald: Justus‐Liebig Uni- Gastroenterology Department, University Hospital of Cruces, Bar-
versity Gießen, Gießen, Germany. Pierluigi Fracasso: Department of akaldo, Bizkaia. Anders Molven: Gade Laboratory for Pathology,
Gastroenterology and Digestive Endoscopy, Ospedale Sandro Pertini, Department of Clinical Medicine, University of Bergen, Bergen,
Local Health Agency Roma 2, Rome, Italy. Helmut Friess: Department Norway; Section for Cancer Genomics, Haukeland University Hos-
of Surgery, TUM School of Medicine and Health, Klinikum rechts der pital, Bergen, Norway. Alexey Okhlobystin: Department of Internal
Isar, Technical University of Munich, Munich, Germany. Jens Disease Propedeutics, Gastroenterology and Hepatology, I.M.
Brøndum Frøkjær: Department of Clinical Medicine, Aalborg Uni- Sechenov First Moscow State Medical University, Moscow, Russia.
versity, Aalborg, Denmark and Department of Radiology, Aalborg Nikola Panic: Faculty of Medicine, University of Belgrade, Belgrade,
University Hospital, Aalborg, Denmark. Luca Frulloni: Department of Serbia; Digestive Endoscopy Unit, University Clinic “Dr Dragisa
Medicine, Pancreas Unit, University of Verona, Verona, Italy. Cristian Misovic‐Dedinje”, Belgrade, Serbia. Andrea Parniczky: Heim Pal Na-
Gheorghe: Center of Gastroenterology & Hepatology, Fundeni Clin- tional Pediatric Institute, Budapest, Hungary; Institute for Trans-
ical Institute, “Carol Davila” University of Medicine, Bucharest, lational Medicine, Medical School, University of Pécs, Pécs, Hungary.
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The following constituted the basis for the design of PICO questions:
1489232
360. Saif MW, Romano A, Smith MH, Rachana P, Valerie R. Chronic use of Observational studies: patients, adults or children with PEI;
long‐acting somatostatin analogues (SSAs) and exocrine pancreatic intervention/exposure, underlying disease, risk factor or mechanism;
insufficiency (EPI) in patients with gastroenteropancreatic neuro- comparator, control population if available; outcome, prevalence,
endocrine tumors (GEP‐NETs): an under‐recognized adverse effect.
clinical consequences.
Cancer Med J. 2020;3(2):75–84. https://doi.org/10.46619/cmj.
2020.3‐1023
Studies on diagnostic tests and diagnostic approaches: patients,
361. McDonald JD, Gupta S, Shindorf ML, Copeland A, Good ML, Sado- adults or children with PEI; intervention, diagnostic test or proced-
wski SM, et al. Pancreatic insufficiency following pancreatectomy: ure; comparator, reference method; outcome, diagnostic accuracy.
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
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Studies on treatment and therapeutic approaches: patients: Fields] OR “fecals”[All Fields] OR “feces”[MeSH Terms] OR “feces”[All
adults or children with PEI; intervention: active treatment or thera- Fields] OR “faecal”[All Fields] OR “fecal”[All Fields]) AND “fat”[All
peutic approach; comparator: either placebo or the standard of care; Fields]) OR ((“coefficiencies”[All Fields] OR “coefficiency”[All Fields]
outcome: efficacy, which is measured in terms of digestion, symptom OR “coefficient”[All Fields] OR “coefficient s”[All Fields] OR “coef-
relief, quality of life, or nutritional improvement, and safety. ficients”[All Fields]) AND “fat”[All Fields] AND (“absorptance”[All
Fields] OR “absorptances”[All Fields] OR “absorption”[MeSH Terms]
S e a r c h s tr a te g y OR “absorption”[All Fields] OR “absorptions”[All Fields] OR
“absorptive”[All Fields] OR “absorptivities”[All Fields] OR “absorpti-
Search of scientific evidence was performed until July 2022 in Medline, vity”[All Fields])) OR ((“nutrition s”[All Fields] OR “nutritional sta-
Embase, Scopus and Cochrane Central Register of Controlled Trial. The tus”[MeSH Terms] OR (“nutritional”[All Fields] AND “status”[All
search strategy in each individual group was as follows. Fields]) OR “nutritional status”[All Fields] OR “nutrition”[All Fields]
OR “nutritional sciences”[MeSH Terms] OR (“nutritional”[All Fields]
Ch a p t e r 1 AND “sciences”[All Fields]) OR “nutritional sciences”[All Fields] OR
“nutritional”[All Fields] OR “nutritionals”[All Fields] OR “nutri-
((((((((“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine tions”[All Fields] OR “nutritive”[All Fields]) AND (“marker”[All Fields]
pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All Fields] OR “markers”[All Fields])) OR (“diagnosis”[MeSH Subheading] OR
AND “pancreatic”[All Fields] AND “insufficiency”[All Fields]) OR “diagnosis”[All Fields] OR “symptoms”[All Fields] OR “diag-
“exocrine pancreatic insufficiency”[All Fields])) AND “pancreatic jui- nosis”[MeSH Terms] OR “symptom”[All Fields] OR “symptom s”[All
ce”[MeSH Terms]) OR (“pancreatic juice”[MeSH Terms] OR (“pan- Fields] OR “symptomes”[All Fields]) OR (“steatorrhoea”[All Fields] OR
creatic”[All Fields] AND “juice”[All Fields]) OR “pancreatic juice”[All “steatorrhea”[MeSH Terms] OR “steatorrhea”[All Fields]) OR (“diar-
Fields] OR (“pancreatic”[All Fields] AND “secretion”[All Fields]) OR rhea”[MeSH Terms] OR “diarrhea”[All Fields] OR “diarrheas”[All
“pancreatic secretion”[All Fields])) AND “malnutrition”[MeSH Terms]) Fields] OR “diarrhoea”[All Fields] OR “diarrhoeas”[All Fields]) OR
OR (“malnutrition”[MeSH Terms] OR “malnutrition”[All Fields] OR (“breath tests”[MeSH Terms] OR (“breath”[All Fields] AND “tests”[All
(“nutritional”[All Fields] AND “deficiencies”[All Fields]) OR “nutri- Fields]) OR “breath tests”[All Fields] OR (“breath”[All Fields] AND
tional deficiencies”[All Fields])) AND “morbidity”[MeSH Terms]) OR “test”[All Fields]) OR “breath test”[All Fields]) OR ((“nutrition s”[All
(“epidemiology”[MeSH Subheading] OR “epidemiology”[All Fields] OR Fields] OR “nutritional status”[MeSH Terms] OR (“nutritional”[All
“morbidity”[All Fields] OR “morbidity”[MeSH Terms] OR “morbid”[All Fields] AND “status”[All Fields]) OR “nutritional status”[All Fields] OR
Fields] OR “morbidities”[All Fields] OR “morbids”[All Fields])) AND “nutrition”[All Fields] OR “nutritional sciences”[MeSH Terms] OR
“mortality”[MeSH Terms]) OR (“mortality”[MeSH Terms] OR “mor- (“nutritional”[All Fields] AND “sciences”[All Fields]) OR “nutritional
tality”[All Fields] OR “mortalities”[All Fields] OR “mortality”[MeSH sciences”[All Fields] OR “nutritional”[All Fields] OR “nutritionals”[All
Subheading]) Fields] OR “nutritions”[All Fields] OR “nutritive”[All Fields]) AND
(“assesed”[All Fields] OR “assesment”[All Fields] OR “assesments”[All
Ch a p t e r 2 Fields])) OR (“weight loss”[MeSH Terms] OR (“weight”[All Fields]
AND “loss”[All Fields]) OR “weight loss”[All Fields]) OR (“body mass
((“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All index”[MeSH Terms] OR (“body”[All Fields] AND “mass”[All Fields]
Fields] AND “pancreatic”[All Fields] AND “insufficiency”[All Fields]) AND “index”[All Fields]) OR “body mass index”[All Fields]) OR
OR “exocrine pancreatic insufficiency”[All Fields]) AND (“diagnosa- (“anthropometries”[All Fields] OR “anthropometry”[MeSH Terms] OR
ble”[All Fields] OR “diagnosis”[All Fields] OR “diagnosis”[MeSH “anthropometry”[All Fields]) OR (“tomography, x ray compu-
Terms] OR “diagnosis”[All Fields] OR “diagnose”[All Fields] OR ted”[MeSH Terms] OR (“tomography”[All Fields] AND “x ray”[All
“diagnosed”[All Fields] OR “diagnoses”[All Fields] OR “diagnosing”[All Fields] AND “computed”[All Fields]) OR “x‐ray computed tomogra-
Fields] OR “diagnosis”[MeSH Subheading])) OR (“pancreatic function phy”[All Fields] OR (“computed”[All Fields] AND “tomography”[All
tests”[MeSH Terms] OR (“pancreatic”[All Fields] AND “function”[All Fields]) OR “computed tomography”[All Fields]) OR (“magnetic
Fields] AND “tests”[All Fields]) OR “pancreatic function tests”[All resonance imaging”[MeSH Terms] OR (“magnetic”[All Fields] AND
Fields] OR (“pancreatic”[All Fields] AND “function”[All Fields] AND “resonance”[All Fields] AND “imaging”[All Fields]) OR “magnetic
“test”[All Fields]) OR “pancreatic function test”[All Fields]) OR resonance imaging”[All Fields]) OR ((“empiric”[All Fields] OR “empir-
((“faecally”[All Fields] OR “fecally”[All Fields] OR “fecals”[All Fields] ical”[All Fields] OR “empirically”[All Fields] OR “empirics”[All Fields])
OR “feces”[MeSH Terms] OR “feces”[All Fields] OR “faecal”[All Fields] AND (“pancreas”[MeSH Terms] OR “pancreas”[All Fields] OR “pan-
OR “fecal”[All Fields]) AND (“elastases”[All Fields] OR “pancreatic creatic”[All Fields] OR “pancreatitides”[All Fields] OR “pan-
elastase”[MeSH Terms] OR (“pancreatic”[All Fields] AND “elasta- creatitis”[MeSH Terms] OR “pancreatitis”[All Fields]) AND (“enzyme
se”[All Fields]) OR “pancreatic elastase”[All Fields] OR “elastase”[All replacement therapy”[MeSH Terms] OR (“enzyme”[All Fields] AND
Fields])) OR (“secretin”[MeSH Terms] OR “secretin”[All Fields] OR “replacement”[All Fields] AND “therapy”[All Fields]) OR “enzyme
“secretins”[All Fields]) OR ((“faecally”[All Fields] OR “fecally”[All replacement therapy”[All Fields]))
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
- 45

C ha p t e r 3 Fields] AND “replacement”[All Fields] AND “therapy”[All Fields]) OR

“enzyme replacement therapy”[All Fields])) AND (“malnu-
((((“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine trition”[MeSH Terms]) OR (“malnutrition”[MeSH Terms] OR “malnu-
pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All Fields] trition”[All Fields] OR (“nutritional”[All Fields] AND “deficiencies”[All
AND “pancreatic”[All Fields] AND “insufficiency”[All Fields]) OR Fields]) OR “nutritional deficiencies”[All Fields])) AND “morbid-
“exocrine pancreatic insufficiency”[All Fields])) AND ((“pan- ity”[MeSH Terms]) OR (“epidemiology”[MeSH Subheading] OR “epi-
creas”[MeSH Terms] OR “pancreas”[All Fields] OR “pancreatic”[All demiology”[All Fields] OR “morbidity”[All Fields] OR
Fields] OR “pancreatitides”[All Fields] OR “pancreatitis”[MeSH “morbidity”[MeSH Terms] OR “morbid”[All Fields] OR “morbid-
Terms] OR “pancreatitis”[All Fields]) AND “enzyme replacement ities”[All Fields] OR “morbids”[All Fields])) AND “mortality”[MeSH
therapy”[MeSH Terms])) OR ((“pancreas”[MeSH Terms] OR “pan- Terms]) OR (“mortality”[MeSH Terms] OR “mortality”[All Fields] OR
creas”[All Fields] OR “pancreatic”[All Fields] OR “pancreatitides”[All “mortalities”[All Fields] OR “mortality”[MeSH Subheading])
Fields] OR “pancreatitis”[MeSH Terms] OR “pancreatitis”[All Fields])
AND (“enzyme replacement therapy”[MeSH Terms] OR (“enzyme”[All C h a pt e r 5
Fields] AND “replacement”[All Fields] AND “therapy”[All Fields]) OR
“enzyme replacement therapy”[All Fields]))) AND (“nutritional sta- (“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All
tus”[MeSH Terms] OR “nutritional sciences”[MeSH Terms])) OR Fields] AND “pancreatic”[All Fields] AND “insufficiency”[All Fields]) OR
(“nutrition s”[All Fields] OR “nutritional status”[MeSH Terms] OR “exocrine pancreatic insufficiency”[All Fields]) AND (“pan-
(“nutritional”[All Fields] AND “status”[All Fields]) OR “nutritional creatitis”[MeSH Terms] OR “pancreatitis”[All Fields] OR (“acute”[All
status”[All Fields] OR “nutrition”[All Fields] OR “nutritional scien- Fields] AND “pancreatitis”[All Fields]) OR “acute pancreatitis”[All
ces”[MeSH Terms] OR (“nutritional”[All Fields] AND “sciences”[All Fields])
Fields]) OR “nutritional sciences”[All Fields] OR “nutritional”[All
Fields] OR “nutritionals”[All Fields] OR “nutritions”[All Fields] OR C h a pt e r 6
“nutritive”[All Fields])
((((((((((((((((((((nutritional intervention[Title/Abstract]) OR (di- ((“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All
etary intervention[Title/Abstract])) OR (dietary therapy[Title/Ab- Fields] AND “pancreatic”[All Fields] AND “insufficiency”[All Fields]) OR
stract])) OR (nutritional therapy[Title/Abstract])) OR (dietary advice “exocrine pancreatic insufficiency”[All Fields]) AND (“pancreatic neo-
[Title/Abstract])) OR (dietary counseling[Title/Abstract])) OR (dietary plasms”[MeSH Terms] OR (“pancreatic”[All Fields] AND “neo-
supplementation[Title/Abstract])) OR (dietary supplements[Title/ plasms”[All Fields]) OR “pancreatic neoplasms”[All Fields] OR
Abstract])) OR (enteral feeding[Title/Abstract])) OR (tube feeding (“pancreatic”[All Fields] AND “cancer”[All Fields]) OR “pancreatic
[Title/Abstract])) OR (parenteral feeding[Title/Abstract])) OR (intra- cancer”[All Fields])) OR ((“pancreas”[MeSH Terms] OR “pancreas”[All
venous feeding[Title/Abstract])) OR (vitamin deficiency[Title/Ab- Fields] OR “pancreatic”[All Fields] OR “pancreatitides”[All Fields] OR
stract])) OR (nutrient deficiency[Title/Abstract])) OR (vitamin “pancreatitis”[MeSH Terms] OR “pancreatitis”[All Fields]) AND “duc-
supplement[Title/Abstract])) OR (nutrient supplement[Title/Ab- tal”[All Fields] AND (“adenocarcinoma”[MeSH Terms] OR “adeno-
stract])) OR (meal plan[Title/Abstract])) OR (dietary plan[Title/Ab- carcinoma”[All Fields] OR “adenocarcinomas”[All Fields] OR
stract])) OR (dietary pattern[Title/Abstract])) OR (nutritional status “adenocarcinoma s”[All Fields])) OR ((“faecally”[All Fields] OR “fecal-
[Title/Abstract])) AND ((pancreatic exocrine insufficiency[Title/Ab- ly”[All Fields] OR “fecals”[All Fields] OR “feces”[MeSH Terms] OR
stract]) OR (exocrine pancreatic insufficiency[Title/Abstract])) “feces”[All Fields] OR “faecal”[All Fields] OR “fecal”[All Fields]) AND
((chronic pancreatitis[Title/Abstract]) AND ((pancreatic exocrine (“elastases”[All Fields] OR “pancreatic elastase”[MeSH Terms] OR
insufficiency[Title/Abstract]) OR (exocrine pancreatic insufficiency (“pancreatic”[All Fields] AND “elastase”[All Fields]) OR “pancreatic
[Title/Abstract]))) AND (((management[Title/Abstract]) OR (inter- elastase”[All Fields] OR “elastase”[All Fields])) OR ((“pancreas”[MeSH
vention[Title/Abstract])) OR (treatment[Title/Abstract]) AND (clin- Terms] OR “pancreas”[All Fields] OR “pancreatic”[All Fields] OR
icaltrial[Filter] OR randomizedcontrolledtrial[Filter])) “pancreatitides”[All Fields] OR “pancreatitis”[MeSH Terms] OR “pan-
creatitis”[All Fields]) AND (“functional”[All Fields] OR “functional s”[All
C ha p t e r 4 Fields] OR “functionalities”[All Fields] OR “functionality”[All Fields] OR
“functionalization”[All Fields] OR “functionalizations”[All Fields] OR
((((“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine “functionalize”[All Fields] OR “functionalized”[All Fields] OR “functio-
pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All Fields] nalizes”[All Fields] OR “functionalizing”[All Fields] OR “functio-
AND “pancreatic”[All Fields] AND “insufficiency”[All Fields]) OR nally”[All Fields] OR “functionals”[All Fields] OR “functioned”[All
“exocrine pancreatic insufficiency”[All Fields])) AND ((“chronic pan- Fields] OR “functioning”[All Fields] OR “functionings”[All Fields] OR
creatitis”[MeSH Terms]) OR (“chronic pancreatitis”[All Fields])) AND “functions”[All Fields] OR “physiology”[MeSH Subheading] OR “phys-
(“enzyme replacement therapy”[MeSH Terms] OR (“enzyme”[All iology”[All Fields] OR “function”[All Fields] OR “physiology”[MeSH
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
46
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Terms])) OR ((“pancreas”[MeSH Terms] OR “pancreas”[All Fields] “pancreatitis”[MeSH Terms] OR “pancreatitis”[All Fields]) AND
OR “pancreatic”[All Fields] OR “pancreatitides”[All Fields] OR “pan- (“resect”[All Fields] OR “resectability”[All Fields] OR “resectable”[All
creatitis”[MeSH Terms] OR “pancreatitis”[All Fields]) AND (“enzyme Fields] OR “resectates”[All Fields] OR “resected”[All Fields] OR
replacement therapy”[MeSH Terms] OR (“enzyme”[All Fields] AND “resecting”[All Fields] OR “resection”[All Fields] OR “resectional”[All
“replacement”[All Fields] AND “therapy”[All Fields]) OR “enzyme Fields] OR “resectioned”[All Fields] OR “resectioning”[All Fields] OR
replacement therapy”[All Fields])) “resections”[All Fields] OR “resective”[All Fields] OR “resects”[All
Fields])) OR (“pancreatectomy”[MeSH Terms] OR “pan-
C ha p t e r 7 createctomy”[All Fields] OR “pancreatectomies”[All Fields]) OR
(“pancreaticoduodenectomy”[MeSH Terms] OR “pan-
((“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All creaticoduodenectomy”[All Fields] OR “pancreatoduodenectomies”
Fields] AND “pancreatic”[All Fields] AND “insufficiency”[All Fields]) [All Fields] OR “pancreatoduodenectomy”[All Fields])
OR “exocrine pancreatic insufficiency”[All Fields]) AND (“cystic
fibrosis”[MeSH Terms] OR (“cystic”[All Fields] AND “fibrosis”[All C h a pt e r 9
Fields]) OR “cystic fibrosis”[All Fields])) OR “CFTR”[All Fields] OR
((“faecally”[All Fields] OR “fecally”[All Fields] OR “fecals”[All Fields] (((“Pancreatic exocrine insufficiency” OR “Exocrine Pancreatic Insuf-
OR “feces”[MeSH Terms] OR “feces”[All Fields] OR “faecal”[All Fields] ficiency” AND English[LA]) NOT (editorial[PT] OR historical article
OR “fecal”[All Fields]) AND (“elastases”[All Fields] OR “pancreatic [PT] OR comment[PT] OR case reports[PT])) NOT („animals“[MeSH]
elastase”[MeSH Terms] OR (“pancreatic”[All Fields] AND “elasta- NOT „humans“[MeSH]))) AND (1960 :2018/11/30[dp]) AND (upper
se”[All Fields]) OR “pancreatic elastase”[All Fields] OR “elastase”[All gastrointestinal surgery OR bariatric surgery OR general surgery OR
Fields])) OR ((“faecally”[All Fields] OR “fecally”[All Fields] OR “fecal- esophagectomy OR gastrectomy OR short bowel syndrome) AND
s”[All Fields] OR “feces”[MeSH Terms] OR “feces”[All Fields] OR (diagnosis OR treatment OR monitoring)
“faecal”[All Fields] OR “fecal”[All Fields]) AND “fat”[All Fields]) OR ((“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocri-
((“pancreas”[MeSH Terms] OR “pancreas”[All Fields] OR “pancreati- ne”[All Fields] AND “pancreatic”[All Fields] AND “insufficiency”[All
c”[All Fields] OR “pancreatitides”[All Fields] OR “pancreatitis”[MeSH Fields]) OR “exocrine pancreatic insufficiency”[All Fields]) AND
Terms] OR “pancreatitis”[All Fields]) AND (“enzyme replacement (“esophagectomy”[MeSH Terms] OR “esophagectomy”[All Fields] OR
therapy”[MeSH Terms] OR (“enzyme”[All Fields] AND “replace- “esophagectomies”[All Fields] OR “oesophagectomies”[All Fields] OR
ment”[All Fields] AND “therapy”[All Fields]) OR “enzyme replacement “oesophagectomy”[All Fields])) OR (“gastrectomy”[MeSH Terms] OR
therapy”[All Fields])) “gastrectomy”[All Fields] OR “gastrectomies”[All Fields]) OR (“bar-
iatric surgery”[MeSH Terms] OR (“bariatric”[All Fields] AND “sur-
C ha p t e r 8 gery”[All Fields]) OR “bariatric surgery”[All Fields]) OR (“gastric
bypass”[MeSH Terms] OR (“gastric”[All Fields] AND “bypass”[All
((“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All Fields]) OR “gastric bypass”[All Fields]) OR ((“gastrics”[All Fields] OR
Fields] AND “pancreatic”[All Fields] AND “insufficiency”[All Fields]) “stomach”[MeSH Terms] OR “stomach”[All Fields] OR “gastric”[All
OR “exocrine pancreatic insufficiency”[All Fields] OR ((“pan- Fields]) AND (“sleeve”[All Fields] OR “sleeved”[All Fields] OR “slee-
creas”[MeSH Terms] OR “pancreas”[All Fields] OR “pancreatic”[All ves”[All Fields] OR “sleeving”[All Fields])) OR ((“duodenitis”[MeSH
Fields] OR “pancreatitides”[All Fields] OR “pancreatitis”[MeSH Terms] OR “duodenitis”[All Fields] OR “duodenum”[MeSH Terms] OR
Terms] OR “pancreatitis”[All Fields]) AND (“dysfunctional”[All Fields] “duodenum”[All Fields] OR “duodenal”[All Fields]) AND (“switch”[All
OR “dysfunctionals”[All Fields] OR “dysfunctioning”[All Fields] OR Fields] OR “switched”[All Fields] OR “switches”[All Fields] OR
“dysfunctions”[All Fields] OR “physiopathology”[MeSH Subheading] “switching”[All Fields] OR “switchings”[All Fields]))
OR “physiopathology”[All Fields] OR “dysfunction”[All Fields]))) AND
((“pancreas”[MeSH Terms] OR “pancreas”[All Fields] OR “pancreati- C h a pt e r 1 0
c”[All Fields] OR “pancreatitides”[All Fields] OR “pancreatitis”[MeSH
Terms] OR “pancreatitis”[All Fields]) AND (“surgery”[MeSH Sub- ((“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All
heading] OR “surgery”[All Fields] OR “surgical procedures, oper- Fields] AND “pancreatic”[All Fields] AND “insufficiency”[All Fields])
ative”[MeSH Terms] OR (“surgical”[All Fields] AND “procedures”[All OR “exocrine pancreatic insufficiency”[All Fields]) AND (“diabetes
Fields] AND “operative”[All Fields]) OR “operative surgical proce- mellitus”[MeSH Terms] OR (“diabetes”[All Fields] AND “mellitus”[All
dures”[All Fields] OR “general surgery”[MeSH Terms] OR (“gen- Fields]) OR “diabetes mellitus”[All Fields])) OR ((“pancreas”[MeSH
eral”[All Fields] AND “surgery”[All Fields]) OR “general surgery”[All Terms] OR “pancreas”[All Fields] OR “pancreatic”[All Fields] OR
Fields] OR “surgery s”[All Fields] OR “surgerys”[All Fields] OR “sur- “pancreatitides”[All Fields] OR “pancreatitis”[MeSH Terms] OR “pan-
geries”[All Fields]))) OR ((“pancreas”[MeSH Terms] OR “pancreas”[All creatitis”[All Fields]) AND (“functional”[All Fields] OR “functional
Fields] OR “pancreatic”[All Fields] OR “pancreatitides”[All Fields] OR s”[All Fields] OR “functionalities”[All Fields] OR “functionality”[All
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
DOMINGUEZ‐MUÑOZ ET AL.
- 47

Fields] OR “functionalization”[All Fields] OR “functionalizations”[All APPENDIX 2

Fields] OR “functionalize”[All Fields] OR “functionalized”[All Fields]
OR “functionalizes”[All Fields] OR “functionalizing”[All Fields] OR C o n fl i c t s o f in t e r e s t
“functionally”[All Fields] OR “functionals”[All Fields] OR “functione-
d”[All Fields] OR “functioning”[All Fields] OR “functionings”[All Fields] The authors listed below report the following conflicts of interest:
OR “functions”[All Fields] OR “physiology”[MeSH Subheading] OR Livia Archibugi—has received honoraria from Viatris
“physiology”[All Fields] OR “function”[All Fields] OR “physi- Georg Beyer—has received honoraria from the Falk Foundation
ology”[MeSH Terms])) OR ((“faecally”[All Fields] OR “fecally”[All Stefanos Bonovas—spouse is an employee of Novartis
Fields] OR “fecals”[All Fields] OR “feces”[MeSH Terms] OR “feces”[All Dmitry Bordin—has received honoraria from Abbott
Fields] OR “faecal”[All Fields] OR “fecal”[All Fields]) AND (“elastase- Laboratories
s”[All Fields] OR “pancreatic elastase”[MeSH Terms] OR (“pancreati- Marco Bruno—has received research grants from Boston Scien-
c”[All Fields] AND “elastase”[All Fields]) OR “pancreatic elastase”[All tific, Pentax Medical, Mylan, AMBU, ChiRoStim, and honoraria from
Fields] OR “elastase”[All Fields])) OR ((“pancreas”[MeSH Terms] OR Boston Scientific, Pentax Medical, AMBU, and Cook Medical
“pancreas”[All Fields] OR “pancreatic”[All Fields] OR “pan- Gabriele Capurso—has received honoraria from Viatris, Amgen,
creatitides”[All Fields] OR “pancreatitis”[MeSH Terms] OR “pan- Boston Scientific, Pangenix
creatitis”[All Fields]) AND (“enzyme replacement therapy”[MeSH Ferdinando D´Amico—has received research grants from Pfizer,
Terms] OR (“enzyme”[All Fields] AND “replacement”[All Fields] AND AbbVie, Ferring, Galapagos, Janssen, and Nestlé, and honoraria from
“therapy”[All Fields]) OR “enzyme replacement therapy”[All Fields])) Sandoz, Janssen, Galapagos, Omega Pharma, Tillotts, and Takeda
OR ((“endocrinal”[All Fields] OR “endocrine system”[MeSH Terms] OR Enrique de‐Madaria—has received research grants from Abbott
(“endocrine”[All Fields] AND “system”[All Fields]) OR “endocrine and Viatris
system”[All Fields] OR “endocrine”[All Fields] OR “endocrines”[All Daniel de la Iglesia Garcia—has received honoraria from Abbott
Fields] OR “endocrinic”[All Fields] OR “endocrinous”[All Fields]) AND and Viatris
(“exocrine pancreatic insufficiency”[MeSH Terms] OR (“exocrine”[All Enrique Dominguez‐Muñoz—has received honoraria from
Fields] AND “pancreatic”[All Fields] AND “insufficiency”[All Fields]) Abbott and Viatris, and research grants from Viatris.
OR “exocrine pancreatic insufficiency”[All Fields] OR (“pancreatic”[All Asbjørn Drewes—has received grants from Digestive Care Inc
Fields] AND “insufficiency”[All Fields]) OR “pancreatic insuffi- and Shionogi, and honoraria from Coloplast, Pangenics, and Shionogi
ciency”[All Fields])) Sinead Duggan—has received research grants from the Meath
Foundation, Department of Public Expenditure & Reform Innovation
C h a p t e r 11 (Government of Ireland), and honoraria from Mylan
Nils Ewald—has received honoraria from Lilly, Novo Nordisk, and
(“Pancreatic Exocrine Insufficiency”[MeSH Terms] OR “pancreatic Novartis
exocrine insufficiency”[All Fields] OR “exocrine insufficiency”[All Pierluigi Fracasso—has received honoraria from Schwabe and
Fields] OR “ageing”[MeSH Terms] OR “ageing”[All Fields] OR “fatty Reckitt
pancreas”[All Fields] OR “non alcoholic fatty pancreas disease”[All Luca Frulloni—has received honoraria from Viatris
Fields] OR “hemochromatosis”[MeSH Terms] OR “hemochromatosi- Andrew Hopper—has received honoraria from Viatris
s”[All Fields] OR “celiac”[MeSH Terms] OR “celiac”[All Fields] OR Pali Hungin—has received research grants from Ricketts and is a
“celiac disease”[All Fields] OR “inflammatory bowel disease”[MeSH member of the ROME Foundation for Functional GI Disorders
Terms] OR “inflammatory bowel disease”[All Fields] OR “irritable Julio Iglesias‐Garcia—has received research grants and honoraria
bowel syndrome”[MeSH Terms] OR “irritable bowel syndrome”[All from Viatris and Abbott
Fields] OR “drug”[All Fields] OR “drug related”[All Fields] OR “rare Jutta Keller—has received a research grant from Canon Medical,
disease”[MeSH Terms] OR “rare disease”[All Fields] OR “inherited and honoraria from Enterra, Falk, GE Healthcare, Medtronic, Mylan,
disease”[All Fields] OR “infectious disease”[MeSH Terms] OR “in- Repha GmbH, Standard Instruments, Takeda
fectious disease”[All Fields] OR “chronic hepatobiliary disease”[All Alexander Kleger—has received honoraria from Sanofi, Sobi, and
Fields] OR “chronic renal disease”[All Fields] OR “chronic uremia”[All Falk Foundation
Fields] OR “chronic kidney disease”[All Fields] OR “somatosta- Andrea Laghi—has received honoraria from Lument, Bracco, GE
tin”[MeSH Terms] OR “somatostatin”[All Fields] OR “pancreatic Healthcare, Geurbet Bayer
tumors”[MeSH Terms] OR “pancreatic tumors”[All Fields] OR José Larino‐Noia—has received honoraria from Viatris and
“chronic heart failure”[MeSH Terms] OR “chronic heart failure”[All Abbott
Fields] OR “Sjogren's syndrome”[MeSH Terms] OR “Sjogren's syn- John Leeds—has received honoraria from Viatris
drome”[All Fields]) AND (“pancreas”[MeSH Terms] OR “pancreas”[All Björn Lindkvist—has received honoraria from Viatris, Takeda,
Fields] OR “pancreatic diseases”[MeSH Terms] OR “pancreatic dis- J. Matthias‐Löhr—has received honoraria from Abbott, Viatris,
eases”[All Fields]) and Nordmark
 20506414, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ueg2.12674 by Cochrane Romania, Wiley Online Library on [30/12/2024]. 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
48
- UNITED EUROPEAN GASTROENTEROLOGY JOURNAL

Emma Martinez‐Moneo—has received honoraria from Viatris Goran Poropat—has received honoraria from Abbott Nutrition,
Julia Mayerle—has received research grants from DFG, BMBF, Fresenius, Sandoz, and Krka Farma
DKH, and honoraria from the Falk Foundation Vinciane Rebours—has received research grants and honoraria
Johanna Ockenga—has received a research grant from the from Mayoly Spindler and Viatris
Innovationsfond, GBA (German government) Jonas Rosendahl—has received honoraria from the Falk Foun-
Alexey Okhlobystin—has received honoraria from Abbott dation, Nordmark, Viatris, Alexxion, MicroTech
Laboratories Oleg Shvets—has received honoraria from Abbott, Takeda, Ber-
Salvatore Paiella—has received honoraria from AlphaTau lin‐Chemie, Nutricia, B.Braun
Medical Hester Timmerhuis—has received honoraria from Viatris and
Lukas Perkhofer—has received research grants from Deutsche Tramedico
Forschungsgesellschaft, German Cancer Aid, and honoraria from Miroslav Vujasinovic—has received honoraria from Viatris and
AstraZeneca, Servier, and Roche Abbott
Mary Phillips—has recieved honoraria from Viatris and Nutricia Michael Wilschanski—has received a research grant from Vertex
Clinical Care Pharmaceuticals, and honoraria from Synspira