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The Relation Between Malnutrition and the Exocrine Pancreas

A Systematic Review

Bartels, Rosalie H.*,†; van den Brink, Deborah A.; Bandsma, Robert H.§; Boele van Hensbroek, Michael*; Tabbers, Merit M.||; Voskuijl, Wieger P.*,†

Journal of Pediatric Gastroenterology and Nutrition: February 2018 - Volume 66 - Issue 2 - p 193–203
doi: 10.1097/MPG.0000000000001769
Review
Free
SDC

Objective: The relation between malnutrition and exocrine pancreatic insufficiency (EPI) has been described previously, but it is unclear if malnutrition leads to EPI or vice versa. We systematically synthesized current evidence evaluating the association between malnutrition and EPI in children.

Methods: Pubmed, Embase, and Cochrane databases were searched from inception until February 2017. We included cohort or case-controlled studies in children reporting on prevalence or incidence of EPI and malnutrition. Data generation was performed independently by 2 authors. Quality was assessed by using quality assessment tools from the National Heart, Lung, and Blood Institute.

Results: Nineteen studies were divided into 2 groups: 10 studies showing EPI leading to malnutrition, and 9 studies showing malnutrition leading to EPI. Because of heterogeneity in design, definitions, and outcome measures, pooling of results was impossible. Quality was good in 4 of 19 studies. Pancreatic insufficiency was linked to decreased nutritional status in 8 of 10 articles, although this link was not specified properly in most articles. In malnourished children, improvement was seen in pancreatic function in 7 of 9 articles after nutritional rehabilitation. The link between the 2 was not further specified. Heterogeneity exists with respect to definitions, outcome measures, and study design.

Conclusions: There is sufficient evidence for an association between EPI and malnutrition. We could not confirm whether there is a correlation or causality between EPI or malnutrition. It was therefore not possible to draw firm conclusions from this systematic review on underlying pathophysiological mechanisms between EPI and malnutrition. More observational clinical trials are crucially needed.

*Global Child Health Group, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands

Department of Pediatrics and Child Health, College of Medicine, University of Malawi, Blantyre, Malawi

Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

§Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Canada

||Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.

Address correspondence and reprint requests to Rosalie H. Bartels, MD, Global Child Health Group, Emma Children's Hospital, Academic Medical Center, Meibergdreef 9, 1100 DD, Amsterdam, The Netherlands (e-mail: r.h.bartels@amc.uva.nl).

Received 3 August, 2017

Accepted 24 September, 2017

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org).

Drs Bartels and van den Brink contributed equally to the article.

The authors report no conflicts of interest.

What Is Known

  • Approximately 45% of worldwide deaths amongst children younger than 5 years are attributable to malnutrition and mortality is strongly related to disturbances in the digestive system.
  • Exocrine pancreatic insufficiency is prevalent in children with malnutrition.
  • Children with chronic diseases such as cystic fibrosis with exocrine pancreatic insufficiency are at known risk for malnutrition.

What Is New

  • This is the first article to systematically review the literature on exocrine pancreatic insufficiency in relation to malnutrition in children.
  • We give a critical appraisal of all published research on this relation.
  • We could not confirm whether there is a correlation or causality between exocrine pancreatic insufficiency and malnutrition.

Undernutrition is a global problem, it contributes to approximately 45% of all deaths in children younger than 5 years, whereas severe malnutrition is a comorbidity in 7.8% of all under 5 deaths in children (1–3).

Malnutrition has been defined in many different ways over the past few decades and encompasses both undernutrition and overweight (1). In this review we will discuss undernutrition only. The current definition of undernutrition is a weight for height (W/H) ≤−2 standard deviations (SDs) and severe malnutrition is defined as a W/H <−3 SD and/or a mid-upper arm circumference of <11.5 cm according to the World Health Organization (WHO) (4). Severe acute malnutrition (SAM) includes 2 different phenotypical forms: nonedematous SAM (severe wasting or “marasmus”) or edematous SAM, which is nutritionally induced bilateral edema (kwashiorkor).

Because mortality in SAM remains high better understanding of the pathophysiology of SAM is needed to improve management.

Severe diarrhea is common in children with SAM, contributes to mortality (5,6) and is not only caused by infections and intestinal epithelial dysfunction relating to malabsorption, but also by impaired pancreatic digestion (7,8). The exocrine pancreas plays a key role in nutrient digestion by secreting digestive enzymes (ie, amylase, lipase, and trypsin) digesting all macronutrients: fat, protein, and carbohydrates (9). Exocrine pancreatic insufficiency (EPI) is the inability to digest nutrients due to severe reduction of digestive enzymes. Its main clinical symptom is steatorrhea caused by the inability to digest fat (9,10). Pancreatic function can be assessed by direct and indirect methods (9). Direct methods are more invasive and include stimulation of the pancreas by secretin, followed by pancreatic duct intubation, collection, and measurement of the secreted enzymes. Indirect tests measure pancreatic enzymes in serum (eg, serum immunoreactive trypsinogen [IRT], lipase, and amylase), in stool (fecal elastase-1 [FE-1] and fecal chymotrypsin [CMT]) or by using breath analysis (9). It is current clinical practice to measure pancreatic function by FE-1 in stool (9).

EPI exists in conditions such as cystic fibrosis (CF), Shwachman-Diamond syndrome (SDS), and chronic pancreatitis (CP) (10–13) and can lead to nutrient malabsorption, undernutrition, poor growth, and mortality (14). In contrast, several older studies, however, mostly performed between 1940 and 1980, have reported that malnutrition in its turn can lead to EPI (15–26). We have recently confirmed these findings and showed a high prevalence of EPI in Malawian children with SAM (93%) (27). It is, however, still not clear how exactly, the relationship between malnutrition and the exocrine pancreas is. More insight into the pathophysiology underlying SAM may aid in lowering the huge malnutrition-related mortality. Therefore, unraveling the association between the exocrine pancreas and malnutrition is of great importance. We systematically assessed the evidence concerning the relation between EPI and malnutrition in children.

We developed the following PICOS: participants: children with malnutrition or EPI; interventions: treatment for malnutrition and or EPI; comparisons: none or healthy controls; outcomes: pancreatic function and nutritional status; study design: systematic review.

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METHODS

Search Strategy

The databases Embase, PubMed, and Cochrane Database of Systematic Reviews were searched from inception to February 2017 (full search strategy and keywords shown in online supplemental information: Appendix 1, Supplemental Digital Content 1, http://links.lww.com/MPG/B127). To identify additional studies, reference lists of relevant studies identified in the literature search were searched by hand. During this process, the exact reporting guidelines as described in the PRISMA statement (www.prisma-statement.org) were followed.

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Study Selection

Two investigators (R.H.B. and D.A.B.) independently reviewed titles and abstracts of all citations in the literature results. Possible relevant studies were retrieved for full-text review. Cohort, randomized controlled trials, or case-controlled studies in children (aged 0–18 years) were included if studies were reporting on prevalence or incidence of EPI or malnutrition. A clear definition and assessment of EPI and malnutrition had to be provided by the authors. Study aim was to determine any relation between EPI and malnutrition. No language restriction was used. Case reports and animal studies were excluded. Disagreements between reviewers were adjudicated by discussion and consensus with two other authors (M.M.T. and W.P.V.).

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Data Extraction and Analysis

For each included trial in the final analysis, data were extracted by using structured data extraction forms, which contained items such as author, participants, definitions of EPI and malnutrition, method of EPI assessment, method of malnutrition assessment, outcomes, and author's conclusions.

Methodological quality of the included articles was assessed using the National Heart, Lung, and Blood Institute quality assessment tool (ie, risk of bias) (28). Three National Heart, Lung, and Blood Institute tools were used: 1 for observational cohort and cross-sectional studies, a second tool for case control studies, and thirdly a separate tool for controlled intervention studies. Using these tools, 2 authors (R.H.B., D.A.B.) independently evaluated the selected articles using “yes,” “no,” “cannot determine,” “not reported,” or “not applicable.” These were discussed and used to frame an overall rating for the quality of each study as “good,” “fair,” or “poor.” Ratings were based on number of quality assessment questions that were confirmed with a “yes”: poor ≤6, fair >6 and <10, and good ≥10 questions answered with “yes.” For the case-control studies that had 12 questions instead of 14 we adjusted the rating: poor ≤5, fair >5 and <9, and good ≥9. A third and fourth author were consulted on any discrepancies between the 2 independent evaluations (M.M.T., W.P.V.)

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RESULTS

Study Search and Quality Assessment

After deducting duplicates, the search strategy and manual search generated 1273 studies that were screened for eligibility (Appendix, Supplemental Digital Content 1, http://links.lww.com/MPG/B127). A total of 1219 were excluded as they were not relevant to our search question (Fig. 1; Flowchart). After evaluating the full text, another 35 studies were excluded for not meeting our inclusion criteria (no clear definition of malnutrition [n = 12], no clear definition of EPI [n = 7], or both [n = 3], different study design [n = 4], full text nonretrievable [n = 1], adult population [n = 6], or not reporting on relation EPI and malnutrition [n = 2]).

FIGURE 1

FIGURE 1

The remaining 19 studies were divided into 2 groups: studies reporting patients diagnosed with EPI who are later found to be malnourished (n = 10) (29–38) and studies reporting patients diagnosed with malnutrition who are later found to have EPI (n = 9) (16,18,21,23,24,27,39–41). Because of heterogeneity in design, definitions, and outcome measures, pooling of results was impossible. Therefore, studies are discussed separately.

Quality assessments are shown in Supplemental Tables 1–3 (Supplemental Digital Content 2–4, http://links.lww.com/MPG/B128, http://links.lww.com/MPG/B129, http://links.lww.com/MPG/B130). Four studies had an overall quality considered to be good (23,29,30,36), 12 were rated to be fair (16,18,24,27,31–33,35,38–41), and the remaining 3 studies were rated to be poor (21,34,37). Only 4 studies did account for key potential confounding variables (24,31,35,41) and just 1 study had a sample size justification (27). Blinding of treatment of participants and researchers was only performed in 1 study (36). Cohen κ was calculated to determine the interobserver variation between the reviewers that assessed the articles using the quality assessment tool (R.H.B. and D.A.B.). There was moderate agreement between the 2 reviewers, κ = 0.602 (95% confidence interval, 0.522–0.682), P < 0.0005 (42). After discussion agreement was reached in 100% of cases.

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Study and Patient Characteristics

In total, 2271 children were included in 19 studies (Table 1) with sample sizes ranging from 13 to 659 children (32,41) Of the included 19 studies, 12 only included children younger than 5 years (16,18,23,24,27,30,32,36–40). These studies were conducted in 13 different countries including resource-high/developed countries: USA, Italy, Australia, France, Poland, UK, and Canada, and resource-poor/developing countries: Egypt, Ivory Coast, Malawi, Senegal, Uganda, and South Africa. Ten studies included patients who were diagnosed with a condition known to be associated with EPI such as CF, SDS, celiac disease, human immunodeficiency virus (HIV), and CP (29–38). Of all studies, Kolodziejczyk et al (35) was the only study which included patients with CP, whereas Carroccio et al (31) solely included HIV-infected children. Three studies included participants diagnosed with SDS (32–34). Celiac disease was studied by 2 separate studies conducted by Carroccio et al (36,37). Lastly 3 studies focused on patients with CF (29,30,38). The remaining 9 studies investigated malnourished children who had either moderate or severe malnutrition (16,18,21,23,24,27,39–41).

TABLE 1

TABLE 1

TABLE 1

TABLE 1

TABLE 1

TABLE 1

TABLE 1

TABLE 1

TABLE 1

TABLE 1

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Pancreatic Function Assessment

The criterion standard test of pancreatic function is the pancreatic stimulation test, “Dreiling tube test” (9,44). This direct pancreatic test was used in 7 studies (16,21,32,34,36,37,39). Cutoff values were provided by the author in 1 of those studies (32), 3 studies used control values of nonmalnourished children (16,21,39), 2 studies used control values of nonceliac children (36,37), and 1 study did not provide any cutoff values at all (34). The current most widely used pancreatic function test is an indirect test measuring faecal levels of zymogen FE-1 (9,45). This was measured in 4 studies, which reported clear cutoff values (27,29,31,33).

Fat malabsorption was reported in 8 studies (16,21,32,34,36,37,39). Of these, Kolodziejczyk et al (35) was the only study using a control group, whereas Bines et al (38) did not report on cutoff values at all. Immunoreactive trypsinogen was tested in 5 studies (24,27,32,40,41), of which 2 were using cutoff values (27,32) and 3 were using a control group (24,40,41). Serum amylase was measured in 5 studies (23,27,31,32,35) with 3 of them also measuring lipase (23,32,35). All reported clear cutoff values except for 1, El-Hodhod et al (23), who used values of a control group. Fecal CMT was assessed in 2 studies with clear cutoff values (31,32). Additional, less commonly used, tests for pancreatic function included ultrasound evaluations (23,33,35), autopsy (18), and endoscopic retrograde cholangio-pancreatography (35).

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Malnutrition Assessment

Assessment of malnutrition was more consistent across the selected articles, with studies using anthropometry, clinical indicators, and albumin as markers of malnutrition. Weight-for-age z scores (WAZ), height-for-age z scores, and/or weight-for-height z scores, currently recommended by WHO for defining malnutrition (46), were used in 14 studies (16,23,24,27,29–33,36–38,40,41). Growth percentiles were used by Hill et al (34) and El-Hodhod et al (23) and a BMI ratio (Cole's ratio: BMI actual/BMI for the 50th centile ×100%) was used to classify malnutrition by Kolodziejczyk et al (35). Four studies used clinical indicators such as pitting edema and skin lesions for malnutrition (16,18,21,39). Lastly albumin was used as a marker of malnutrition by 4 studies, of which 3 used controls but El-Hodhod et al (23) did not have cutoff values (16,30,37).

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Group 1: Articles Reporting Patients Diagnosed With Exocrine Pancreatic Insufficiency Who Are Later Found to be Malnourished

Eight out of 10 studies describe the association between EPI and malnutrition (29,30,32–36,38). Quality assessment was rated “poor” for 2 studies (34,37), “fair” for 5 studies (31–33,35,38), and “good” for 3 studies (29,30,36). Cohen et al (29) reported that CF children with no pancreatic activity (n = 75/84) (FE-1 <15 μg/g) had a significantly lower WAZ and more fat malabsorption compared to CF children with residual activity (n = 9/84) (FE-1 ≥15 μg/g). Significantly greater fat malabsorption in pancreatic insufficient CF children (n = 16/29) versus pancreatic sufficient CF patients (n = 13/29) was also reported by Bronstein et al (30), which was significantly correlated with a decrease in WAZ. Bines et al (38) reported that pancreatic insufficiency (found in n = 35/46 CF children) was strongly associated with poor weight and length gains (Supplemental Table 4, Supplemental Digital Content 5, http://links.lww.com/MPG/B131) (29–37).

All 3 studies of children with SDS, reported high numbers of EPI, (Pichler et al 95.2%, Cipolli et al 100%, Hill et al 100%) (32–34). Of these, Cipolli et al had the highest proportion of malnourished children (n = 11/13, 84%). This study followed up 6 children at a mean age of 10 years, and found a significant increase in both weight and height z scores, although unclear if on pancreatic enzyme replacement therapy (PERT) or not (from −3.8 to −1.4 and from −3.6 to −1.8, respectively, both P < 0.001) (32). Hill et al (34) reported that 64% (n = 7/11) had a weight below the 3rd percentile but did not report on anthropometry during follow-up. Pichler et al (33) reported only 33% (n = 7/21) to be malnourished and on follow-up of unclear duration only 38% (n = 5/13) experienced catch up growth. Pichler et al described that poor nutritional status in SDS is multifactorial and can be caused by several other factors than EPI, such as feeding difficulties (in 43% (n = 9/21) of their population) and enteropathy (50% n = 7/14). None of the 3 SDS studies demonstrated a direct correlation between EPI and malnutrition.

Carroccio et al (31) found EPI in 30% of HIV-infected children and a significant correlation between EPI and fat malabsorption. Only 14% (n = 2/14) of patients with EPI had SAM and no direct correlation between was mentioned. In children with CP, 25% (n = 52/208) was malnourished and this was only significantly correlated with a higher age of onset of CP, but not with fat absorption (35).

In 2 different studies also carried out by Carroccio et al (36,37) pancreatic function in children with celiac disease was studied. In 1 study, they found EPI in 29% (n = 15/52) of the celiac children and 37% of the patients (n = 19/52) had SAM but no correlation between the 2 was reported (37). In the other study they investigated the effect of pancreatic enzyme therapy in children with celiac disease, and showed that 38% (n = 15/40) suffered from EPI and 15% (n = 6/40) from severe EPI (36). Celiac patients who were given pancreatic enzymes had a significant increase in weight after 30 days of therapy, compared to those who did not receive therapy, but this difference disappeared after supplementation of 60 days.

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Group 2: Articles Reporting Patients Diagnosed With Malnutrition Who Are Later Found to Have Exocrine Pancreatic Insufficiency

All 9 studies described some association, but not always causality, between malnutrition and EPI (16,18,21,23,24,27,39–41). Quality assessment was rated “poor” for 1 study (21), “fair” for 7 studies (16,18,24,27,39–41), and “good” for 1 study (23). Seven studies reported that EPI in children with malnutrition is correctable after nutritional rehabilitation (16,18,21,23,24,27,39). El-Hodhod et al (23) showed that malnourished children (n = 33) had significantly lower serum amylase, serum lipase, and pancreatic head size compared to a group of normally nourished controls (n = 12), and a significant improvement was seen in all measures of pancreatic function and weight after nutritional rehabilitation (23). Barbezat and Hansen (16) examined pancreatic enzyme markers in gastric juice and found these to be significantly lower in children with kwashiorkor (n = 14) and marasmus (n = 7) than in healthy controls (n = 7), and these enzymes to significantly improve after nutritional rehabilitation. Durie et al (24) reported a significant correlation between severity of malnutrition (n = 50) and IRT, with IRT reverting to normal in patients with improvement in nutritional status. Although no statistical values were provided, Thompson and Trowell (18) also showed that children with kwashiorkor had lower levels of amylase and lipase compared to controls and that these improved after nutritional rehabilitation (18). In a study conducted in Ivory Coast and France, Sauniere et al (21) concluded that in children with kwashiorkor (n = 25) pancreas function (based on a total of 5 different enzymes) was significantly decreased compared to healthy African (n = 11), and European children (n = 62) and that this disappeared after refeeding. A second study by Sauniere and Sarles (39) discussed pancreatic function in malnourished children in Dakar (n = 13) and Abidjan (n = 15) in West Africa, which was decreased compared to healthy children in France. After nutritional rehabilitation pancreatic secretion levels significantly increased but remained subnormal in the children from Abidjan and no improvement was found in children from Dakar. This was similar to our own previous study in which we found EPI in 92% (n = 71/77) and severe EPI in 77% (n = 59/77) of children with SAM and also found a significant improvement but no normalization of pancreatic function after nutritional rehabilitation (27). In addition, we found the degree of EPI to be significantly worse in children with kwashiorkor compared to children with marasmus (median FE-1 of 22 vs 80 μg/g) and elevated IRT levels in 28% (n = 11/39) of the patients (Supplemental Table 5, Supplemental Digital Content 6, http://links.lww.com/MPG/B132) (16,18,21,23,24,27,39–41).

Two studies reported on EPI in malnourished Australian Aboriginal children (40,41). Similar to Durie et al, Cleghorn et al (40) also reported on pancreatic damage in children with malnutrition, demonstrated by a significant correlation between IRT and degree of malnutrition (n = 78/198 moderately and n = 63/198 severely malnourished). Briars et al also found increased IRT levels related to decreased weight z scores but no relation to other nutritional indices such as arm circumference and skinfold thickness. A potential confounder could have been gastroenteritis in these patients potentially causing elevated IRT (41).

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DISCUSSION

This is the first systematic review evaluating the association between EPI and malnutrition in children. Because malnutrition contributes to a high mortality in children younger than 5 years worldwide, it is of great importance to explore potential new ways of treating malnutrition and reducing mortality. This systematic review shows that there is sufficient evidence for an association between EPI and malnutrition. Both EPI leading to malnutrition and malnutrition leading to EPI have been demonstrated in children in the existing literature.

We refrained from a quantitative (pooled) analysis due to the heterogeneity of the data. In addition to providing an overview of the existing literature it was not possible to draw firm conclusions on the exact link between EPI and malnutrition (correlation, causality, association).

All studies describing EPI leading to malnutrition were conducted in cohorts of patients with an underlying disease: CF, CP, SDS, HIV, and celiac disease (29–38). Only 2 studies reported on the degree of EPI correlating with poor nutritional status (29,30). Carroccio et al (37), emphasized that in celiac disease has both feature of EPI and malnutrition but no causality was reported. The other studies only mentioned EPI and malnutrition but did report on a correlation.

Although the exact etiology of EPI may vary, it is common practice nowadays to treat EPI with PERT. An improvement of nutritional status after PERT was described by 2 studies and demonstrates the influence of EPI on malnutrition (29,36). Controversially, Pichler et al (33) found that in SDS patients catch-up growth was poor despite PERT. All other included studies did not report on how PERT affected nutritional status.

Most of the studies describing malnutrition leading to EPI were conducted in a low resource setting (16,18,21,23,27,39). A varying degree of improvement of EPI after nutritional rehabilitation was reported by 7 studies, which is indicative of nutritional status influencing pancreatic function (16,18,21,23,24,27,39). Durie et al (24) describe elevated IRT levels normalizing after 3 weeks to 1 year, Thompson and Trowell (18) report on differences in enzymes after 7 days to 51 days, Sauniere et al (21) reports on normalization after several months and Bartels et al (27) report on improvement of FE-1 levels only a few days after the first measurement. These differences in EPI improvement can be partly explained by differences in treatment duration.

This systematic review was complicated by the differences in criterion standard and the definitions used. In addition to this, the majority of the included studies have methodologically shortcomings in terms of sample size, design, outcome measures, and statistical analysis, or used techniques that are not the (current) criterion standard. The pancreatic stimulation test, a direct test, is considered the criterion standard for the assessment of exocrine pancreatic function (9). The studies included using pancreatic stimulation test are published between 1952 and 1999 (16,18,21,32,34,36,37,39). It is not commonly used anymore because of the many disadvantages: it is invasive, impractical, burdensome to patients, and requires radiation exposure to verify positioning (9). An indirect pancreatic tests using FE-1 currently is the most widely used test: it is noninvasive, biochemically stable, and has high sensitivity (9). Not surprisingly, this test was used in more recent studies (27,29,31,33). Many other different indirect tests, all less sensitive and specific for EPI than FE-1, were used as well contributing to the heterogeneity. Most studies measured serum pancreatic enzymes (16,18,21,23,24,27,31,32,34,39–41). Abnormally low serum enzymes may indicate EPI, but these markers have low sensitivity and specificity for EPI and only support a diagnosis (9). Fecal CMT, used in 2 studies (31,32), is also less sensitive than FE-1 and requires discontinuation of PERT (9). Fecal fat absorption, assessed in 8 studies (24,29–32,34–38), is not specific for EPI as other factors also result in a positive test (diet, malabsorption, gut transit) (9). Other ways of measuring EPI used such as imaging and post-mortem studies are nonspecific to EPI and are of limited diagnostic value.

Definitions of EPI and cutoff values for EPI were not consistent across studies. Several studies used healthy control groups as a comparison to estimate abnormal function instead of internationally established cutoff values.

A third limitation contributing to heterogeneity was the various ways of defining malnutrition. Only 1 study (27) defined malnutrition according to the most recent WHO guidelines (W/H ≤−3 SD (4)), 4 studies defined malnutrition as a W/H ≤−2 SD (32,33,40,41), and all other studies defined it in different ways or used only clinical signs (in kwashiorkor patients). Finally, as there is a risk of publication bias as we were unable to identify unpublished potential negative data on the association between EPI and malnutrition.

In conclusion, this systematic review showed that there is sufficient evidence for an association between EPI and malnutrition. We could not, however, confirm whether this is a correlation or causality and therefore it was not possible to draw firm conclusions on underlying pathophysiological mechanisms between EPI and malnutrition. More observational clinical trials are crucially needed and future studies investigating EPI and malnutrition should investigate the potential role of PERT in malnourished children.

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Acknowledgments

The authors would like to express our special thanks to Arnold Leenders, librarian at the Academic Medical Center of Amsterdam, the Netherlands.

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    Keywords:

    exocrine pancreatic insufficiency; global child health; pancreatic function; severe malnutrition

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