ARTICLE
Auteur(s) : NA Benahmed, D Manene, L Barbot, N Kapel
Laboratoire de coprologie fonctionnelle, APHP, Groupe
hospitalier Pitié-Salpêtrière, Paris
Article reçu le 10 Juin 2008, accepté le 29 Juin 2008
Direct function test performed after stimulation with secretin
and cholecystokin, and collection of pancreatic secretions for
H+, bicarbonate and enzyme analysis is the most accurate
method for the evaluation of exocrine pancreatic function, and is
therefore still considered by many investigators as the gold
standard for pancreatic investigation [1]. However, this method is
time-consuming, expensive and cannot be used in infants due to its
invasive character. The measurement of pancreatic proteases in
feces is thus generally preferred in the pediatric routine because
of its low invasiveness [2]. For several years, determination of
fecal chymotrypsin has been used as an accepted indirect test for
exocrine pancreatic function [3]. More recently, numerous studies
have shown the better sensitivity of pancreatic elastase-1 (E1)
determination for the evaluation of pancreatic function [4]. Fecal
E1 determination is thus of routine use in infant population
presenting with a neonatal diagnosis of cystic fibrosis or in
infants with poor weight gain and growth in order to precociously
detect pancreatic insufficiency (PI). In neonate population, low
levels of fecal elastase can be observed during the first weeks of
life due to pancreatic maturation deficit, especially in preterms.
However, previous data have shown that E1 levels currently
normalize within one month [5, 6]. There are few data regarding the
value of one spot measure of elastase to assess pancreatic status
in this population. The aim of this retrospective study was to
analyze the follow-up of fecal elastase measurement during the
first 2 years of life in a non selected population of infants.
Patients and methods
This retrospective study included all fecal elastase assays
performed from February 2000 until February 2008 in infants of less
than 2 years. For each of them, 1 to 14 stool samples were
successively analyzed. Pancreatic E1 concentration was determined
using a “sandwich” type enzyme immunoassay (Schebo-Biotech,
Guiessen, Germany) which combines the use of two monoclonal
antibodies binding to 2 distinct epitopes specific to human
pancreatic E1. Results were expressed as μg/g of stool. Using this
assay, the limit of detection was 15 μg/g of stool and 200
μg/g of stool was considered as the lower normal limit. Results are
given as median (range). Data were analyzed using the Statview
(Abacus® Concepts, Berkeley, CA) statistical software
package and statistical comparisons were performed using the
Fisher’s exact test.
Results
This study processed 2655 samples issued from 2245 patients; 157
samples were excluded from analysis due to their meconial origin (n
= 8) or because insufficient information concerning the sampling
date (n = 149). Only one spot measure was performed in 1940
patients. E1 concentration was below the detection limit in 224
patients; between 15 and 100 μg/g in 90 patients, between
100 and 200 μg/g in 89 patients and over 200 μg/g (normal
cut-off) in 1537 patients (no PI).
A follow-up with 2 to 14 samples per patient (median: 2) was
performed in 236 infants (110 females, 126 males) aged between 5 to
674 days at the day of enrolment (first sample), thus allowing the
measurement of E1 in 562 samples. E1 was over 200 μg/g in a
first sample obtained at day 195 (7-674) in 122 patients (51.7% of
patients) and below 200 μg/g in the first sample obtained at
day 73 (5-606) in 114 patients. There was no significant difference
in the age of infants at the time of first sampling in those 2
groups.
Fecal E1 levels remained over the normal limit in the successive
samples (2 to 4 samples analysed per patient, median: 2) in 104/122
infants (= 85.2% of patients presenting with a first normal
measurement) whereas an alteration was observed in 18 infants
(14.8% of these patients) at day 207 (15-569). E1 levels were below
25, 100 and 200 μg/g in 5, 6 and 7 infants respectively,
leading to the diagnosis of PI. There was no significant difference
in the age of those infants at the time of PI diagnosis.
In 114 patients, the first measurement of E1 was below
200 μg/g. In those patients, fecal E1 was undetectable in 44
samples at day 45 (7-515); between 15 and 100 μg/g in 33
samples obtained at day 90 (9-488) and between 100 and
200 μg/g in 37 samples obtained at day 85 (5-606). There was
no significant difference in the infant’s age at the time of this
first sampling in those 3 groups of patients. In this population,
62/114 (54.4%) had a confirmed PI with E1 concentrations below
200 μg/g at the end of follow-up. This abnormal pancreatic
functionality was observed in 38/44 infants (86.4%) with a first E1
level below 15 μg/g. In this population, E1 was undetectable
in 36 infants and below 25 μg/g in the remaining 2 infants at
the end of the follow-up. In contrast, only 16/33 infants with a
first E1 concentration below 100 μg/g (48.5%) and 8/37 infants
with a first E1 concentration below 200 μg/g (21.6%) remained
with PI during the follow-up.
In the remaining population, a normalization of fecal E1 was
observed i.e. 52/114 infants (45.6%). Only 6/44 infants with a
first undetectable E1 level had a normal level at the end of the
follow-up (median: J437, range: 73-577) whereas 17/33 infants with
first concentration between 15 and 100 μg/g (51.5%) and 29/37
with first concentration between 100 and 200 μg/g (78.4%) had
a normal E1 concentration at the end of the follow-up which
occurred at J117 (9-488) and J101 (25-581) in those two groups,
respectively.
Discussion
The assessment of pancreatic function within the youngest pediatric
population is of fundamental importance to provide precocious
enzyme support so the evaluation of non invasive marker is a major
challenge in this population. In our study, 236 infants without any
information about clinical state, aged 5-674 day-old at the day of
inclusion were longitudinally tested for fecal E1 for the detection
of PI. In this population, 122 infants had a normal E1
concentration in the first sample. No significant variation of this
E1 levels was observed in 85.2% of infants whereas 14.8% of those
infants displayed abnormal fecal E1 concentrations at the end of
the follow-up allowing the diagnosis of moderate to severe PI. No
correlation between age of diagnosis and seriousness of PI was
observed. Walkowiak et al. have studied the progression of
pancreatic insufficiency during the first year of life in cystic
fibrosis infants carrying two severe mutations [7]. In those
patients, abnormal E1 (< 100 μg/g) concentrations were
found in all infants at 6 months of age. Our retrospective study
shows that PI, even severe ones with undetectable fecal E1
concentrations, can be detected as latter as 428 days of life. In
contrast to what is currently observed in adult and children
populations [8, 9], a special attention thus should be given to the
analysis of E1 concentrations in infants as a precocious diagnosis
of pancreatic insufficiency (PI) is crucial for the early
introduction of a pancreatic enzyme replacement therapy which will
prevent further consequence of malabsorption. One spot measure does
not totally exclude PI in this population (figure 1).
In our population, 114 infants exhibited low E1 levels in the
first sample which further normalized in 45.6% of the population.
We and others have reported a physiological pancreatic
insufficiency in preterm neonates, normal levels being observed in
preterm and full-term neonates at the second week of life [5, 6,
10]. This study shows that maturation of pancreatic function may be
delayed and occur all along the two first years of life. It appears
to be rarely observed when fecal E1 is undetectable in a first
sample but highly probable in infants displaying a moderate PI in a
first sample taken before the age of 2 years. Even in infants with
E1 concentration below 100 μg/g, normalization of pancreatic
function can be observed within 2 years although a cut-off level of
100 μg/g had shown a very high predictive value in ruling out
malabsorption in older cystic fibrosis children [11]. Control
measurements are thus required for those infants within the two
first years of life in order to confirm PI. Moreover, we must keep
in mind that low E1 concentrations can be observed in liquid stools
and in patients with intestinal villous atrophy.
References
1 Kitagawa M, Naruse S, Ishiguro H, Nakae Y,
Kondo T, Hayakawa T. Evaluating exocrine function tests
for diagnosing chronic pancreatitis. Pancreas 1997; 15: 402-8.
2 Goldberg DM. Proteases in the evaluation of pancreatic
function and pancreatic disease. Clin Chim Acta 2000; 291:
201-21.
3 Brown GA, Sule D, Williams J, Puntis JW,
Booth IW, McNeish AS. Faecal chymotrypsin: a reliable
index of exocrine pancreatic function. Arch Dis Child 1988; 63:
785-9.
4 Stein J, Jung M, Sziegoleit A, Zeuzem S,
Caspary WF, Lembcke B. Immunoreactive elastase I:
clinical evaluation of a new noninvasive test of pancreatic
function. Clin Chem 1996; 42: 222-6.
5 Campeotto F, Kapel N, Kalach N, et al. Low
levels of pancreatic elastase 1 in stools of preterm infants. Arch
Dis Child Fetal Neonatal Ed 2002; 86: F198-F199.
6 Nissler K, Von Katte I, Huebner A,
Henker J. Pancreatic elastase 1 in feces of preterm and term
infants. J Pediatr Gastroenterol Nutr 2001; 33: 28-31.
7 Walkowiak J, Sands D, Nowakowska A, et al.
Early decline of pancreatic function in cystic fibrosis patients
with class 1 or 2 CFTR mutations. J Pediatr Gastroenterol Nutr
2005; 40: 199-201.
8 Molinari I, Souare K, Lamireau T, et al.
Fecal chymotrypsin and elastase-1 determination on one single stool
collected at random: diagnostic value for exocrine pancreatic
status. Clin Biochem 2004; 37: 758-63.
9 Naruse S, Ishiguro H, Ko SB, et al. Fecal
pancreatic elastase: a reproducible marker for severe exocrine
pancreatic insufficiency. J Gastroenterol 2006; 41: 901-8.
10 Kori M, Maayan-Metzger A, Shamir R,
Sirota L, Dinari G. Faecal elastase 1 levels in premature
and full term infants. Arch Dis Child Fetal Neonatal Ed 2003; 88:
F106-F108.
11 Beharry S, Ellis L, Corey M, Marcon M,
Durie P. How useful is fecal pancreatic elastase 1 as a marker
of exocrine pancreatic disease? J Pediatr 2002; 141: 84-90.
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