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).
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).
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.
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).
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.
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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exocrine pancreatic insufficiency; global child health; pancreatic function; severe malnutrition
Supplemental Digital Content
© 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,