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Pancreatic exocrine insufficiency after pancreatic resection: a systematic review

BMC Surgery volume 25, Article number: 53 (2025) Cite this article

Abstract

Introduction

Pancreatic exocrine insufficiency (PEI) is a condition defined by a reduction in pancreatic exocrine activity that impairs normal digestion. Despite established guidelines recommendations, precise diagnosis of PEI after pancreatic resection are infrequently achieved. This review aims to provide a comprehensive overview of the methodology and accuracy of diagnostic tools available for evaluating PEI after pancreatic resection.

Methods

A review of PEI diagnostic tests was conducted using a combined text and MeSH search strategy to identify relevant articles focused on post-pancreatectomy PEI diagnosis.

Results

The literature search yielded 4,874 records, and 30 studies were included in the analysis, with a total of 2,305 patients. The reported frequency of PEI across the included studies varied widely, though more than two-thirds of included papers reported an incidence of PEI above 65% in patients who underwent pancreatoduodenectomy or distal pancreatectomy. The faecal elastase-1 (FE-1) test was the most frequently used test for diagnosing post-pancreatectomy PEI. Six studies compared the diagnostic accuracy of FE-1 with faecal fat tests or 13 C breath tests, finding no significant differences. Five studies reported on micronutrient deficiencies.

Conclusion

The FE-1 test is the most commonly used diagnostic tool for post-pancreatectomy PEI; however, well-designed studies comparing the diagnostic accuracy of various tests for PEI are lacking. Additionally, few studies report on micronutrient deficiencies, variations in anthropometric data or PEI-related patient-reported outcomes. Future studies should aim to establish a gold standard for diagnosis and severity assessment of post-pancreatectomy PEI and provide guidance for tailored pancreatic enzyme replacement therapy.

Peer Review reports

Introduction

Pancreatic exocrine insufficiency (PEI) is a condition defined as a reduction of pancreatic exocrine activity in the intestine at a level that prevents normal digestion [1]. It is characterised by gastrointestinal symptoms such as diarrhoea, steatorrhea (fatty stools), and deficiencies in essential fats and fat-soluble vitamins (A, D, E, and K) [2]. Reports suggest prevalence rates of 70–90% after pancreatoduodenectomy (PD) and 20–50% after distal pancreatectomy (DP). However, estimating the true prevalence of PEI is difficult due to the limitations of diagnostic tests and to the challenges in distinguishing it from other causes of post pancreatectomy diarrhoea or malnutrition [3].

According to clinical guidelines [1, 3,4,5,6,7,8,9,10,11,12,13], the diagnosis of PEI relies on a combination of symptom assessment and laboratory tests. Laboratory tests are categorized into direct pancreatic secretion tests and indirect pancreatic function tests, aiming to provide a more objective assessment of pancreatic exocrine function. Imaging techniques, like magnetic resonance cholangiopancreatography (MRCP) and computed tomography (CT), are used to identify structural causes of PEI.

Test based on direct measurements of pancreatic secretions are the most accurate but are invasive and time-consuming. These involve stimulating the pancreas, collecting pancreatic juices, and analysing them for bicarbonate concentration and digestive enzymes [14]. These tests are more commonly used for diagnosing early-stage chronic pancreatitis rather than post-pancreatectomy PEI. The most widely used indirect test is the faecal elastase-1 (FE-1) test, which is non-invasive and relatively inexpensive [15,16,17]. It measures the levels of elastase-1 in stool, which correlates with pancreatic enzyme production. Despite its utility, the FE-1 test has limitations, such as being less accurate with mild PEI and requiring formed or semi-formed stool for accurate results [18]. Other indirect tests include measuring serum pancreatic enzyme levels in stool or urine sample, such as chymotrypsin, which is unreliable if there is ongoing pancreatic inflammation [3]. Breath tests can diagnose PEI by measuring diminished fat digestion in the intestine. These tests involve ingesting triglycerides labelled with non-radioactive 13–14 C, which are broken down by pancreatic enzymes. The resulting 13CO2 or 14CO2 is measured in exhaled breath [4, 19]. These tests have the advantage of directly measuring pancreatic enzyme-specific digestion but require several hours of breath collection. Finally, steatorrhea can be precisely assessed by the determination of faecal fat. However, the diagnostic test involves a burdensome process of ingesting a diet with known fat content over five days, whose compliance can influence the accuracy of the test, and collecting stool samples for fat measurement over the last three days [20].

In clinical practice, despite established guidelines, precise diagnosis of pancreatic insufficiency after pancreatic resection are infrequently achieved. Consequently, pancreatic enzyme replacement therapy (PERT) is often initiated at a standard dosage, regardless of individual patient characteristics, confirmation of PEI diagnosis, or severity. The present review aims to provide a comprehensive overview of the methodology and accuracy of diagnostic tools available for evaluating PEI in patients undergoing different types of pancreatic resection.

Methods

Search strategy

The search was undertaken according to the PRISMA guidelines [1]. Two researchers systematically searched Medline, EMBASE and the Cochrane Library for reports published before the 8th of February 2024, not limited to the English language, using a combined text and MeSH search strategy. The search terms for the literature review contained the terms “pancreatic exocrine insufficiency, “PEI” and “surgery”. A snapshot on clinical guidelines published over the last 10 years on diagnostic tools for PEI was prepared using the search strategy. The search was further broadened by extensive cross-checking of all the references in the articles retrieved to identify eventual additional non-indexed literature.

Study selection

Studies included in the review met the following criteria: (a) patients older than 18 years old; (b) patients who underwent any type of pancreatic surgery; (c) experimental or observational (prospective and retrospective) studies regarding the diagnosis of PEI.

Exclusion criteria were: experimental studies on animal models, case series, case reports, reviews, editorials and comments were excluded. When duplicate reports from the same study were identified, only the most recent publication or the one with the longest follow-up period was included. The full text of each article was assessed if it was not excluded in the initial review. If the perioperative outcomes were not reported or were impossible to extract from each of the two groups, the studies were excluded.

Data collection

Four researchers (MDM, AHR, AS and GS) assessed titles and abstracts of selected studies to determine their eligibility in Rayyan web app for systematic reviews (https://www.rayyan.ai/). Full articles were selected for further assessment. Inconsistencies were resolved through discussion until a consensus was reached. The extracted data included: country of study, design, number of participants included, age, sex; method of diagnosis; type of surgery; use of perioperative chemotherapy; use of pancreatic enzyme replacement therapy; methods of the diagnostic test used; reference level reported, months of follow-up. Disagreements over data extraction were resolved by consensus between the authors.

Evaluation of studies and statistical analysis

Two researchers (AS and MDM) independently evaluated included studies for quality assessment according to the Newcastle-Ottawa Scale (NOS) [21]: scores ≥ 7–9, between 4 and 6 and < 4 were considered low, intermediate, and high risk, respectively. The data were described as proportions and median along with a corresponding minimum-maximum range.

Results

The literature search yielded 4,874 records, and after excluding duplicates and conducting title screening, 4,696 records were excluded due to study characteristics and methodology. The full-text articles of 78 papers were assessed for eligibility. Exclusion reasons included methodological issues and lack of data on primary outcomes. Ultimately, 30 studies were included in the analysis [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51] with a total of 2305 patients (Fig. 1).

Figure. 1
figure 1

Flow chart of included studies

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No randomised clinical trial (RCT) was found; 12 papers were based on prospective registries [25, 27, 29, 31,32,33, 35, 42,43,44, 46, 48], and 18 on retrospective studies (Table 1) [22,23,24, 26, 28, 30, 34, 36,37,38,39,40,41, 45, 47, 49,50,51]. Only six papers [24, 25, 27, 37, 38, 43] compared the accuracy of two different diagnostic tools for post-pancreatectomy PEI evaluation, and all of them used FE-1 as the reference standard for the comparison. None of the included studies employed matching statistical analysis techniques. The mean age of the participants ranged from 50 to 69 years. The mean follow-up ranged from 1 month to 10 years.

Table 1 Characteristics of included papers
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Only one of the included studies was considered at low risk of bias [27], two were at high risk of bias [29, 44], and the remaining 27 [22,23,24,25,26, 28, 30,31,32,33,34,35,36,37,38,39,40,41,42,43, 45,46,47,48,49,50,51] at intermediate risk (Supplementary Table 1).

None of the included papers used a test based on a direct measurement of pancreatic secretions as a reference standard for the diagnosis of PEI, preferring indirect measurements instead. Table 2 provide detailed information on sample collection and reference values used in included papers. Stool tests, specifically FE-1 measured in a stool sample, were used in 19 out of 30 included papers [22, 24, 25, 27, 31,32,33, 35,36,37,38,39, 42, 43, 45, 46, 48,49,50]. Data were consistent in defining normal values as FE-1 > 200 mg/g. Two papers [34, 41] measured faecal chymotrypsin, collected either from a stool sample or over a 72-hour period; in both cases, normal values were considered to be faecal chymotrypsin > 6 U/g. Three papers [24, 25, 27] measured faecal fat: patients needed to follow specific dietary requirements, stool samples were collected over a 72-hour period, and a coefficient of fat absorption (CFA) > 93% or a faecal fat excretion (FFE) < 6–7 g/day were taken as indicative of normal pancreatic exocrine function. Breath tests were used in eleven included papers [23, 26, 28,29,30, 37, 38, 40, 43, 44, 51], with different cut-off values depending on the substrate administered. Finally, one paper measured the N-benzoyl-L-tyrosyl-p-aminobenzoic acid (BT-PABA) recovered in a urine sample, diagnosing PEI as urinary BT-PABA < 70% of the administered dose.

Table 2 Description of test used as reference standard for diagnosis of PEI from included papers
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Reported incidence of PEI according to the surgical procedure performed and the test used

The reported frequency of PEI from included papers presented a very wide range, between 26 and 100% of patients submitted to pancreatic resection. Only two papers reported an incidence below 30% [26, 34]; eight reported and incidence between 30 and 60% [26, 29, 30, 37, 40, 41, 49, 51], while in the remaining it was above 60%.

The frequency of PEI was then assessed according to the type of pancreatic resection performed and the test used for the diagnosis of PEI. Eighteen [22,23,24, 28, 30,31,32, 36,37,38,39, 41, 43,44,45,46,47, 50] papers assessed patients who underwent PD, only one assessed patients who underwent DP [49], and the remaining eleven [25, 27, 29, 33,34,35, 38, 40, 42, 48, 51] evaluated patients who underwent both PD and DP.

As shown in Table 3, the reported incidence of PEI from papers evaluating outcomes of PD ranged from 47 to 100%. The paper describing the frequency of PEI in patients who underwent DP reported an incidence of only 59%. Papers assessing the incidence of PEI in both PD and DP reported an incidence ranging from 26 to 100%.

Table 3 Reported incidence of PEI according to the to the test used and the surgical procedure performed
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Papers reporting on PEI after PD described an incidence ranging from 47 to 100% when using FE-1 [22, 24, 31, 32, 36, 37, 39, 43, 45, 46, 50] and 47–82% when using the 13 C breath test [23, 29, 30, 37, 38, 43, 44]. Other tests described a wider range of PEI frequency, between 36 and 86% [24, 41, 47]. Papers reporting on the frequency of PEI after pancreatic resection, without specifying the type of resection, described an incidence of PEI between 65 and 100% using FE-1 [25,26,27, 33, 35, 42, 48] and 54–69% using the 13 C breath test [26, 28, 40, 51]. As above, other tests included in the analysis reported a wider range of frequency, ranging from 26 to 100% [25, 27, 34].

Comparative studies, micronutrient deficiency, weight lost and time to recover weight

A total of six comparative papers were included in the analysis [24,25,26,27, 37, 43]. As shown in Table 4 Three of these compared FE-1 with faecal fat tests [24, 25, 27] while the other three compared FE-1 with 13 C breath tests [26, 37, 43]. Reported sensitivity, specificity and diagnostic accuracy of tests are detailed in Table 4. Only one paper [26] specifically aimed to evaluate the diagnostic accuracy of the two tests. They suggested that findings from the 13 C breath correlated with the FE-1 test, however, the former showed higher incidence and accuracy in the diagnosis of PEI; therefore, it could be more useful in the assessment of pancreatic exocrine function after pancreatic resection.

Table 4 Comparative studies on incidence of PEI after pancreatic resection
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Five papers [23, 24, 31, 37, 42] reported on micronutrient deficiencies. In two cases [31, 37] the studies measured levels of vitamins A, D, E, and K, and in one case [31] levels of iron, copper, zinc, serum retinol, alpha-tocopherol, and vitamin C were also assessed. Although many of the included papers mentioned weight measurement, changes in body weight, time to recover weight, and other anthropometric measurements were not used as clinical outcomes in any of the studies.

Snapshot on current guidelines recommendations

A total of seven clinical guidelines or consensus documents were found regarding recommendations for diagnostic tools for PEI [1, 4, 8,9,10,11,12,13]. Only one [12] focused specifically on patients who underwent pancreatic resection, while the other four provided general recommendations for patients with possible PEI. A summary of the guidelines’ recommendations, including the grade of evidence when available, is reported in Table 5. Overall, the FE-1 test was consistently recommended by the included guidelines as recommended test. It was suggested that stool samples should be adjusted for water content when possible, and additional markers of malnutrition and measurements of micronutrients should be considered to support unclear diagnosis of PEI.

Table 5 Snapshot on current guidelines recommendations on recommendations for diagnostic test for pancreatic exocrine insufficiency
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Discussion

PEI is a frequent complication after pancreatic surgery. Despite the wide heterogeneity and low quality of the included papers, more than two-thirds of them reported an incidence above 65% in patients who underwent PD or DP. The FE-1 test was the most frequently used test for the diagnosis of post-pancreatectomy PEI, as consistently recommended by the most recent clinical guidelines [1, 4, 8,9,10,11,12,13]. Very few studies compared the diagnostic accuracy of tests for post-pancreatectomy PEI. Additionally, very few studies reported on micronutrient deficiencies, variation in anthropometric data or time to recover weight. Whether PEI is a valid surrogate outcome for malnutrition and nutritional deficiency after pancreatic surgery remains to be determined and whether available diagnostic tests can capture the entire spectrum of this issue is still to be determined.

Patients after pancreatic resections frequently present malnutrition with significant weight loss and struggle to recover from that. Currently available investigations mainly focus on PEI defined by diagnostic tools such as of CFA, FFE, FE-1 elastase test or the 13 C breath test. Direct measurement of excreted pancreatic enzymes is rarely used, due to its invasive nature, complexity of and impracticality following PD. Similarly, the measurement of CFA or FFE, that require a specific dietary regimen over a period or three days, whose compliance can alter test results and is rarely used in the clinical practice. As shown by the present review the FE-1 elastase or the 13 C breath test were used in 26 out of 30 included papers with a wide range of reported incidence after both PD and DP. However, reliable data on their sensitivity, specificity, and diagnostic accuracy remain sparse. When evaluated, stool-based tests such as CFA and FFE but also more subjective clinical signs like steatorrhea, were used as reference standards for diagnostic accuracy [25,26,27]. Therefore, the present analysis highlights not only the absence of precise data on definition and incidence of PEI after pancreatic resection but also lack of data on diagnostic accuracy of available test and of an agreement on a reference standard for its diagnosis. Other relevant issues to be considered when addressing this issue are also local availability, reproducibility and cost-effectiveness of available diagnostic tools in the real practice. These aspects remain only partially addressed in the current literature.

Also, whether PEI correctly reflect patients’ malnutrition status and serves as an adequate surrogate outcome for patient-reported outcomes following pancreatic resection remain controversial. The influence on the changes of anthropometric data after pancreatic surgery of specific micronutrient deficiencies remains an unexplored issue. Similarly, time to recover weight after surgery, which is a relevant clinical indicator as it is frequently related to patient functional recovery is seldom assessed. Tools such as the PEI Questionnaire (PEI-Q), developed by Johnson et al. [52], designed to assess patient reported symptoms and impact on health-related quality of life are rarely included in papers assessing post-pancreatectomy PEI. The present review confirmed the lack of solid data on these aspect in included papers.

As a measure to limit the malnutrition clinical guidelines recommend the universal utilisation of pancreatic enzyme replacement from the early the post-pancreatectomy recovery period [1, 3,4,5,6, 12, 53]. However, their utilization is not always able to completely resolve patients’ symptoms. While malnutrition may seem relatively less clinically relevant compared to post-operative mortality or major complications, it can still influence the time to start and the type of adjuvant chemotherapy protocol. Additionally, the patient-perceived quality of life, especially in subjects whose life expectancy frequently does not exceed 24–36 months, should not be underestimated. What is still missing from the current available literature is a post-pancreatectomy personalised nutrition assessment according to patient- or procedure-related risk factors, including post-operative complications.

A reliable diagnostic test for PEI, both pre- and post-pancreatectomy, would be invaluable for achieving accurate diagnosis and personalized supplementation therapy. With a precise diagnostic tool, clinicians could identify true PEI cases, quantify severity, and prescribe tailored PERT. This is particularly relevant, as current data indicate that approximately 30% of patients may not require PERT. Reducing unnecessary PERT prescriptions would not only prevent potential side effects for patients without confirmed PEI but also lower costs for healthcare systems [54, 55]. In light of recent international shortages of PERT, optimizing prescriptions becomes even more critical [56]. A robust, widely accessible PEI test could thus enhance patient management and resource efficiency, ensuring PERT supplies are directed to those with verified needs and potentially reducing the impact of supply constraints on patient care. Several limitations should be considered in the context of the present review. There was a considerable degree of heterogeneity in the methods of included studies and baseline characteristics of the included patients. A possible selection bias in postoperative assessment should also be considered, as patients who do not survive a year, travel to the hospital, and undergo a period of starvation and hold pancreatic enzyme replacement therapy are likely to have been excluded from included studies. Therefore, there is likely to be a recruitment bias towards fitter, younger patients with less aggressive pathology. Additionally, there was a lack of relevant data on patient-reported outcomes, the diagnostic accuracy of PEI tests, and the reference standard diagnostic tools for post-pancreatectomy PEI. Improved diagnostic and treatment strategies for post-pancreatectomy malnutrition, including PEI and micronutrient deficiencies, as well as patient-reported outcomes related to PEI, need to be developed. Future research should aim to better capture the full spectrum of post-pancreatectomy malnutrition, aiming to identify a gold standard for the diagnosis of this clinical issue. Additionally, research should stratify potential risks for specific groups of patients and focus on time to weight and functional recovery after pancreatic surgery.

Conclusions

Post-pancreatectomy PEI presents a significant health challenge. The faecal elastase-1 (FE-1) test was the most used diagnostic tool. However, well-designed studies comparing the diagnostic accuracy of different tests for post-pancreatectomy PEI are lacking. Additionally, few studies reported on micronutrient deficiencies, variations in anthropometric data, weight recovery time, and PEI-related patient-reported outcomes. Future research should aim to establish a gold standard for diagnosis and severity assessment of post-pancreatectomy PEI, evaluate risks across patient groups and provide guidance for tailored pancreatic enzyme replacement therapy.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

BP-PABA:

N-Benzoyl-L-Tyrosyl-P-Aminobenzoic acid

CT:

Computed tomography

CFA:

Coefficient Of fat absorption

DP:

Distal pancreatectomy

FE-1:

Faecal elastase-1

FFE:

Faecal fat excretion

MRCP:

Magnetic resonance cholangiopancreatography

NOS:

Newcastle-ottawa scale

PD:

Pancreatoduodenectomy

PEI:

Pancreatic exocrine insufficiency

PEI-Q:

PEI Questionnaire

PERT:

Pancreatic enzyme replacement therapy

RCT:

Randomised clinical trial

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Authors and Affiliations

  1. Department of Health Sciences, University of Piemonte Orientale, Novara, 28100, Italy

    Marcello Di Martino, Andrea Saibanti & Matteo Donadon

  2. Division of Surgery, University Maggiore Hospital della Carità, Corso Mazzini 18, Novara, 28100, Italy

    Marcello Di Martino, Andrea Saibanti & Matteo Donadon

  3. Department of Surgery, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Madrid, Spain

    Ángela de la Hoz Rodriguez, Guillermo Salvador Camarmo & Elena Martín-Pérez

  4. Division of Gastroenterology, University Maggiore Hospital della Carità, Novara, 28100, Italy

    Nico Pagano

Authors
  1. Marcello Di Martino
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  2. Ángela de la Hoz Rodriguez
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  3. Andrea Saibanti
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  4. Guillermo Salvador Camarmo
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  6. Elena Martín-Pérez
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  7. Matteo Donadon
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Contributions

Marcello Di Martino: Conceptualization; data curation; formal analysis; investigation; methodology; software; validation; writing – original draft; writing – review &editing. Ángela la Hoz Rodriguez: Conceptualization; data curation; formal analysis; investigation; validation; writing – review & editing. Andrea Saibanti: data curation; formal analysis; investigation; software; validation; writing – original draft; writing – review &editing. Guillermo Salvador Camarmo: Data curation; software; visualization; writing – original. Nico Pagano: Data curation; visualization; writing – original draft. Elena Martín-Pérez: Conceptualization; investigation; methodology; supervision; validation; writing – review & editing. Matteo Donadon: Conceptualization; investigation; methodology; supervision; validation; writing – review & editing.

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Correspondence to Marcello Di Martino or Matteo Donadon.

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Di Martino, M., de la Hoz Rodriguez, Á., Saibanti, A. et al. Pancreatic exocrine insufficiency after pancreatic resection: a systematic review. BMC Surg 25, 53 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12893-025-02787-y

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BMC Surgery

ISSN: 1471-2482

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