Scandinavian Journal of Gastroenterology

ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20

Prevalence and determinants of exocrine

pancreatic insufficiency among older adults:
Results of a population-based study

Dietrich Rothenbacher, Michael Löw, Philip D. Hardt, Hans-Ulrich Klör,

Hartwig Ziegler & Hermann Brenner

To cite this article: Dietrich Rothenbacher, Michael Löw, Philip D. Hardt, Hans-Ulrich Klör,
Hartwig Ziegler & Hermann Brenner (2005) Prevalence and determinants of exocrine pancreatic
insufficiency among older adults: Results of a population-based study, Scandinavian Journal of
Gastroenterology, 40:6, 697-704, DOI: 10.1080/00365520510023116

To link to this article: https://doi.org/10.1080/00365520510023116

Published online: 08 Jul 2009.

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 Scandinavian Journal of Gastroenterology, 2005; 40: 697
/704

ORIGINAL ARTICLE

Prevalence and determinants of exocrine pancreatic insufficiency

among older adults: Results of a population-based study

DIETRICH ROTHENBACHER1, MICHAEL LÖW1, PHILIP D. HARDT2,

HANS-ULRICH KLÖR2, HARTWIG ZIEGLER3 & HERMANN BRENNER1
1
Department of Epidemiology, German Centre for Research on Ageing, University of Heidelberg, Heidelberg, Germany, 2Third
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Medical Department, Justus-Liebig University Giessen, Giessen, Germany, and 3Gesundheitsberichterstattung Saarland
/
Krebsregister, Saarbrücken, Germany

Abstract
Objective. The prevalence and main determinants of exocrine pancreatic insufficiency were investigated in a large
population-based sample of older adults by measuring pancreatic elastase-1 in stool. Material and methods. The study
comprised 914 participants aged 50 to 75 years recruited by their general practitioner during a general health examination.
All participants and their physicians were asked to fill out a standardized questionnaire which contained information on
socio-demographic and lifestyle factors as well as medical history. Native stool was examined for pancreatic elastase-1 with a
commercially available ELISA (ScheBo† Tech, Giessen, Germany). Results. Overall, 524 women and 390 men aged 50 to
75 years (mean age 61.9 years) were included in the analysis. In total, 105 (11.5%) of the 914 subjects showed signs of
exocrine pancreatic insufficiency (EPI) with 5/200 m g elastase-1/g stool, and 47 (5.1%) subjects showed signs of a severe
exocrine pancreatic insufficiency (SEPI, B/100 m g elastase-1/g stool). There was a clear increase in EPI with age. Patients
taking angiotensin-converting enzyme (ACE) inhibitors had a lower prevalence than subjects without this medication; these
associations persisted after adjustment for covariates. Conclusions. Prevalence of EPI increases with age and seems to be
tentatively higher in men than in women. However, smoking seems to be an independent risk factor for EPI and SEPI
whereas ACE-inhibitor intake might be a protective factor. The latter finding may even point to new options in the
treatment of chronic pancreatitis.

Key Words: Elastase-1, exocrine pancreatic insufficiency, observational study, prevalence, risk factors

Introduction parameter in assessment of exocrine pancreatic

A wide variety of tests, both direct and indirect, are
available to evaluate pancreatic function [1].
Whereas direct tests are usually accurate, they are
usually of an invasive nature, expensive, uncomfor-
table for the patient and only applicable in a clinical
setting. However, for several years now a non-
invasive, specific test to evaluate exocrine pancreatic
function has been available [2]. Pancreatic elastase-1
is a pancreas-specific protease that undergoes mini-
mal changes during intestinal transit and it can be
readily measured in stool samples [3]. In contrast to
other non-invasive tests, such as chymotrypsin,
elastase-1 is stable and unaffected by exogenous
pancreatic enzyme substitution. It is a reliable
function [1,4,5] and is currently the best test to
assess the prevalence of pancreatic dysfunction on a
population-based level.
Data describing the burden of exocrine pancreatic
insufficiency (EPI) in the general population are
sparse so far. According to a recent review [6] the
annual incidence of chronic pancreatitis was esti-
mated to be 3.5
/4.0 per 100,000 in Western
countries. Besides referral centre series and clinical
samples, which have been highly selective, large
unselected population-based samples have rarely
been investigated so far.
We estimated the prevalence of EPI in a large
population-based sample of older adults by means of
faecal pancreatic elastase-1 measurements, and we

Correspondence: Dietrich Rothenbacher, MD, MPH, Department of Epidemiology, German Centre for Research on Ageing, University of Heidelberg,
Bergheimer Str. 20, DE-69115 Heidelberg, Germany. Tel: /49 62 2154 8146. Fax: /49 62 2154 8142. E-mail: rothenbacher@dzfa.uni-heidelberg.de

(Received 22 September 2004; accepted 22 December 2004)

ISSN 0036-5521 print/ISSN 1502-7708 online # 2005 Taylor & Francis
DOI: 10.1080/00365520510023116
 698 D. Rothenbacher et al.
examined the main determinants using a multi-
variate analysis strategy.
Material and methods
Study design and study population
This study was carried out in the context of the
baseline examination of a large-scale, population-
based, cohort study (ESTHER /‘‘Epidemiologische
Studie zu Chancen der Verhütung, Früherkennung
und optimierten Therapie chronischer Erkrankun-
gen in der älteren Bevölkerung’’) with the aim of
evaluating new approaches to the prevention and
early detection of chronic diseases among older
adults.
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The ESTHER study, which has been approved by
local and regional ethics committees, is conducted in
Saarland, a state located in South-West Germany.
Between July 2000 and December 2002, 9958
inhabitants of Saarland, aged 50 to 75 years, were
recruited by their general practitioner during a
general health examination offered biennially to
older adults in Germany.
Data collection
All participants and their physicians were asked to
complete a standardized questionnaire containing
information on socio-demographic and lifestyle fac-
tors as well as medical history. The physicians
provided information on medication of each patient
and filled in brand names, doses and dose instruc-
tions of currently prescribed drugs in a structured
questionnaire. Drugs were attributed to preparations
available on the German market and linked to the
‘‘Gelbe Liste-Pharmindex’’ (MediMedia, Neu-Isen-
burg, Germany) providing the active compounds
and anatomic therapeutic chemical (ATC) codes [7].
In addition, patients were asked to mail a stool
sample to the study centre for laboratory analyses
which was mainly used to extract DNA from stool.
The current study focuses on a subsample of 914
participants for whom a sample of native, solid stool
from the original probe was available after DNA
extraction; the sample was stored at /708C and
later examined for pancreatic elastase-1. This sub-
sample did not differ from the whole study popula-
tion with respect to the distribution of gender and
age and can be regarded as a (quasi-) random sample
as it was only determined by the amount of stool in
the container that was sent to the laboratory.
Laboratory analysis
We used a commercially available ELISA (ScheBo†
Tech, Giessen, Germany) using two monoclonal
antibodies binding to two distinct epitopes of this
enzyme. The following cut-off points have been
established in numerous clinical trials (for an over-
view see Table VI): normal levels: /200 m g
elastase
/1/g stool, moderate EPI: 100
/200 mg
elastase
/1/g stool, severe exocrine pancreatic insuf-
ficiency (SEPI): B/100 mg elastase-1/g stool.
Statistical methods
The subsample with faecal pancreatic elastase-1
measurements and the whole cohort of the
ESTHER study were described with respect to the
main socio-demographic characteristics. Prevalence
of EPI and SEPI was determined according to age
and gender. In addition, the association of EPI
(EPI and SEPI) with age and gender and the
following potential determinants was assessed calcu-
lating a x2 statistic: duration of school education
( 5/9 years, /9 years), self-reported alcohol con-
sumption (none, B/60 g/week, 60
/140 g/week,
/140 g/week), smoking status (never, former,
current), body mass index (B/25 kg/m2, 25
/27.5
kg/m2, /27.5
/30 kg/m2, /30 kg/m2), history of
diabetes mellitus (no, yes (no-insulin treatment), yes
(insulin treatment)), history of hyperlipidaemia (no,
yes), history of gallstones (no, yes), history of
cholecystectomy (no, yes). In addition, the regular
intake of the following medications for which poten-
tial side effects on exocrine pancreatic function were
considered was evaluated: antidiuretics (no, yes),
angiotensin-converting enzyme (ACE) inhibitors
(no, yes), non-steroidal anti-inflammatory drugs
(NSAIDs) (no, yes), statins (no, yes). If the expected
cell number was less than 5, then Fisher’s exact test
was used.
We then used multivariate logistic regression with
a backward variable selection procedure to identify
the independent association of various factors with
EPI and SEPI. All the variables listed above were
considered in the initial model. We then eliminated
step by step all variables that did not contribute to
the model in a statistically significant way (p /0.1).
Odds ratios (OR) and 95% confidence intervals (CI)
were calculated for all variables included in the final
model. The analyses were carried out with the SAS
statistical software package (version 8.02).
Results
Overall, 914 participants aged 50 to 75 years were
included in this analysis (Table I) and the subsample
with faecal pancreatic elastase-1 measurements was
similar to the overall ESTHER study population.
The mean age of the study sample was 61.9 (SD
6.67) years. 57.3% were female, 71.1% had a school
 Exocrine pancreatic insufficiency among older adults 699
Table I. Main socio-demographic characteristics of the study
A history of diabetes was reported by 11.4% and a
population with faecal elastase-1 test result and of the whole
ESTHER cohort. history of hyperlipidaemia by 45.8%.
Table II shows the prevalence of EPI (defined as
N (%) Study N (%) ESTHER 5/200 mg elastase-1/g stool) and the prevalence of
cohort cohort SEPI ( B/100 m g elastase-1/g stool) according to age
Age (years) (Ntotal /914) (Noverall /9958) and gender. Overall, 11.5% of the 914 subjects
Mean (SD) 61.9 (6.67) 62.1 (6.63)
showed signs of EPI and 5.1% of SEPI indicated
by faecal elastase-1 measurements. The prevalence
Age
50
/54 years 167 (18.3%) 1712 (17.2%) was tentatively higher in men than in women (EPI
55
/59 years 150 (16.4%) 1689 (17.0%) 13.6% versus 9.9%, p /0.08, SEPI 5.9% versus
60
/64 years 261 (28.6%) 2704 (27.2%) 4.6%, p/0.36).
65
/69 years 194 (21.2%) 2278 (22.9%) There was a clear increase in EPI with age, from
70
/75 years 142 (15.5%) 1564 (15.7%)
6.0% in the 50
/54 years age group to 15.5% in the
Gender
65
/69 years age group, and 13.4% in the 70
/75
Female 524 (57.3%) 5471 (54.9%)
Male 390 (42.7%) 4487 (45.1%) years age group (p/0.005 after adjustment for
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Duration of school education

gender). This increase was similar in SEPI, but the
5/9 years 666 (71.1%) 7245 (74.7%) respective cell numbers were much smaller for the
Alcohol consumption latter. The patterns for age were less clear
None 309 (36.8%) 3147 (34.2%) among men than among women and statistically
B/60 g/week 229 (27.3%) 2610 (28.4%) significant among women only in gender-specific
60
/140 g/week 189 (22.5%) 2227 (24.2%) analyses.
/140 g/week 112 (13.4%) 1222 (13.3%)
We then investigated the association of various
Smoking status (cigarettes)
factors with prevalence of EPI and SEPI (Table III).
Never 483 (54.1%) 4918 (50.7%)
Former 257 (28.8%) 3129 (32.3%) Duration of school education showed no association
Current 153 (17.1%) 1652 (17.0%) with prevalence of EPI or SEPI. For alcohol
History of diabetes mellitus consumption, subjects who reported drinking less
Yes 104 (11.4%) 1069 (11.4%) than 60 g alcohol per week had the lowest prevalence
History of hyperlipidaemia (EPI 7.4%, SEPI 3.1%), and subjects who reported
Yes 369 (45.8%) 3996 (44.4%) drinking more than 140 g per week had the highest
prevalence (EPI 13.4%, SEPI 5,4%) but the differ-
ences among levels of alcohol consumption were not
education of 9 years or less. With respect to alcohol statistically significant. Current cigarette smoking
consumption, over a third of the participants re- was tentatively associated with a higher prevalence of
ported to be abstainers, 27.3% reported drinking EPI and SEPI, whereas body mass index, history of
less than 60 g ethanol per week, 22.5% between 60 diabetes (tentatively highest in subjects taking in-
and 140 g and 13.4% over 140 g per week (mean in sulin with a prevalence of EPI of 17.7% and SEPI of
the latter group: 261 (SD 159) g per week); 17.1% 5.6%), a history of gallstones or cholecystectomy
reported that currently they were cigarette smokers. showed no statistically significant associations with
Table II. Prevalence of exocrine pancreatic insufficiency (EPI, B/200 mg elastase/1/g stool) and of severe pancreatic insufficiency (SEPI,
B/100 mg elastase/1/g stool) according to gender and age.

Prevalence (n (%)) of pancreatic insufficiency

Female (n/524) Male (n /390) All (n/914)

EPI SEPI EPI SEPI EPI SEPI

Age 5/167 (3.0%)

50
/54 years 4/97 (4.1%) 1/97 (1.0%) 6/70 (8.6%) 4/70 (5.7%) 10/167 (6.0%)
55
/59 years 3/86 (3.5%) 0/86 (0%) 10/64 (15.6%) 7/64 (10.9%) 13/150 (8.7%) 7/150 (4.7%)
60
/64 years 18/149 (12.1%) 9/149 (6.0%) 15/112 (13.4%) 4/112 (3.6%) 33/261 (12.6%) 13/261 (5.0%)
65
/69 years 17/110 (15.5%) 9/110 (8.2%) 13/84 (15.5%) 5/84 (6.0%) 30/194 (15.5%) 14/194 (7.2%)
70
/75 years 10/82 (12.2%) 5/82 (6.1%) 9/60 (15.0%) 3/60 (5.0%) 19/142 (13.4%) 8/142 (5.6%)
*p /0.009 *p/0.009 p/0.7 *p /0.4 p /0.005$ p/0.12
All 52/524 (9.9%)% 24/524 (4.6%)§ 53/390 (13.6%)% 23/390 (5.9%)§ 105/914 (11.5%) 47/914 (5.1%)

*Fisher’s exact test.

$
After adjustment for gender; %p -value for difference according to gender 0.08; §p -value for difference according to gender 0.36.
 700 D. Rothenbacher et al.
Table III. Association of socio-demographic, lifestyle and medical factors with exocrine pancreatic insufficiency (EPI,B/200 m g elastase
/1/g
stool) and severe exocrine pancreatic insufficiency (SEPI,B/100 m g elastase
/1/g stool).

Factor Prevalence (n (%)) of EPI p -value Prevalence (n (%)) of SEPI p -value

School education
5/9 years 78/666 (11.8%) 32/666 (4.8%)
/9 years 21/220 (9.6%) 0.4 12/220 (5.5%) 0.7
Alcohol consumption
None 34/309 (11.0%) 19/309 (6.2%)
B/60 g/week 17/229 (7.4%) 7/229 (3.1%)
60
/140 g/week 22/189 (11.6%) 9/189 (4.8%)
/140 g/week 15/112 (13.4%) 0.3 6/112 (5.4%) 0.4
Smoking status (cigarettes)
Never 45/483 (9.3%) 20/483 (4.1%)
Former 0/257 (11.7%) 12/257 (4.7%)
Current 24/153 (15.7%) 0.09 13/153 (8.5%) 0.09
Body mass index
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B/25 kg/m2 23/241 (9.5%) 11/241 (4.6%)

25-27.5 kg/m2 22/199 (11.2%) 10/199 (5.0%)
/27.5
/30 kg/m2 27/199 (13.6%) 13/199 (6.5%)
/30 kg/m2 31/261 (11.9%) 0.6 12/261 (4.6%) 0.8
History of diabetes mellitus
No 90/810 (11.4%) 42/810 (5.2%)
Yes, no insulin 12/118 (10.5%) 5/118 (4.2%)
Yes, insulin treatment 3/17 (17.7%) 0.6 1/17 (5.6%) 0.9
History of hyperlipidaemia
No 78/621 (12.6%) 40/621 (6.4%)
Yes 27/293 (9.2%) 0.1 7/293 (2.4%) 0.01
History of gallstones
No 82/763 (10.8%) 37/763 (4.9%)
Yes 23/151 (15.2%) 0.1 10/151 (6.6%) 0.4
History of cholecystectomy
No 92/797 (11.5%) 41/797 (5.1%)
Yes 13/117 (11.1%) 0.9 6/117 (5.1%) 1.0

prevalence of EPI and SEPI in the bivariate analysis. The bivariate associations between various medi-
A history of hyperlipidaemia was associated with cations that were suspected of being potentially
both a lower prevalence of EPI and of SEPI (the associated with pancreatitis and EPI and SEPI are
latter was statistically significant). listed in Table IV. Notably, treatment with ACE

Table IV. Association of intake of various medications with exocrine pancreatic insufficiency (EPI, B/200 m g elastase
/1/g stool) and severe
exocrine pancreatic insufficiency (SEPI, B/100 m g elastase
/1/g stool).

Medication Prevalence (n (%)) of EPI p -value Prevalence (n (%)) of SEPI p -value

Antidiuretics
No 93/827 (11.3%) 43/827 (5.2%)
Yes 12/87 (13.8%) 0.5 4/87 (4.6%) 0.8
ACE inhibitors
No 90/724 (12.4%) 44/724 (6.1%)
Yes 15/190 (7.9%) 0.08 3/190 (1.6%) 0.01
NSAIDs
No 101/893 (11.3%) 47/893 (5.3%)
Yes 4/21 (19.1%) 0.1* 0/21 (0%) 0.6*
Statins
No 98/843 (11.6%) 45/843 (5.3%)
Yes 7/71 (9.9%) 0.7 2/71 (2.8%) 0.5*

Abbreviations: ACE/angiotensin-converting enzyme; NSAIDs/non-steroidal anti-inflammatory drugs.

*Fisher’s exact test.
 Exocrine pancreatic insufficiency among older adults 701

inhibitors showed a tentative inverse association with
prevalence of EPI (7.9% versus 12.4%, p /0.08)
and a significant inverse association with SEPI
(1.6% versus 6.1%, p /0.01).
Table V shows the results of the multivariate
logistic regression after taking all the aforementioned
variables into the initial model and applying a
backwards selection strategy. As the final model
shows, increasing age was a clear determinant for
EPI and SEPI as already seen in the bivariate
analysis. Current smokers also showed a statistically
significant increased OR for EPI (OR 2.06 (95% CI
1.19
/3.57)) and SEPI (OR 2.39 (95% CI 1.14
/
5.02)). Subjects who took ACE inhibitors (according
to the physicians’ information) showed a consider-
ably lower odds for EPI compared to other subjects
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smoking. In addition, ACE-inhibitor intake ap-
peared to be a preventive factor and may point to
an interesting new treatment option for chronic
pancreatitis.
So far, there are few data on the prevalence of EPI
at the population-based level. Estimated incidence
rates of chronic pancreatitis in adulthood ranged
from 1.6 new cases per year per 100,000 subjects in
Switzerland to 23 per year per 100,000 in Finland
[8], and a hospital-based study from Germany
estimated a prevalence of 6.4 cases per 100,000
inhabitants [9]. A nationwide clinical survey from
Japan estimated a prevalence of 29 cases per 100,000
[10] with a higher rate in men compared to women.
The estimates of the annual incidence would result
in an estimated cumulative prevalence between 1

(OR 0.55 (95% CI 0.31
/0.99)). The inverse asso- and 20 cases per thousand subjects (1 to 2%) in a
ciation with ACE-inhibitor intake was even more group of subjects aged 70 years.
pronounced for SEPI (OR 0.23 (95% CI 0.07
/ However, all previous estimates had been based on
0.77)). No other variables met the criteria for clinical studies (using invasive methods that can
inclusion in both models. hardly be applied in a population-based sample) or
autopsy studies [6,8
/12]. Both may be difficult to
generalize as they are based on clinical subjects with
Discussion
diagnosed disease or fatal diseases, and the relation-
This population-based study of 914 asymptomatic ship to the source population is usually difficult to
subjects aged 50 to 75 years who had undergone a assess and essentially unknown. In contrast, our
routine health screening examination suggests that study is the first one conducted on a population-
the prevalence of pancreatic insufficiency as deter- based sample, and we have no indication that it is
mined by means of faecal elastase-1 measurements not representative of the general population in this
might be higher in the general population than age group.
previously estimated. The prevalence increased The faecal elastase-1 test seems to be a useful and
with age, was tentatively higher in men than in reliable non-invasive test to describe exocrine pan-
women and was positively associated with cigarette creatic function with a sufficient test performance in
the context of an epidemiological study (for a
Table V. Main determinants of pancreatic insufficiency as deter-
summary of test performance, see Table VI [3
/5,
mined by means of unconditional logistic regression. 13
/19]) and a good sensitivity for the detection of
moderate to severe chronic pancreatitis has been
Odds ratio (95% CI) reported. According to some studies, faecal elastase-
1, however, showed less sensitivity for mild to
Factors* For EPI$ For SEPI% moderate chronic pancreatitis [4,13,14,16,17]. As
Age a note of caution, most of the available studies have
50
/54 years 1Reference 1Reference been small and estimates prone to random variation.
55
/59 years 1.66 (0.70
/3.94) 1.84 (0.57
/6.00) In addition, heterogeneous patient groups had been
60
/64 years 2.79 (1.31
/5.92) 2.27 (0.78
/6.63) included in some of the studies.
65
/69 years 3.67 (1.70
/7.93) 3.59 (1.23
/10.53)
Based on the test characteristics as described in
70 */75 years 3.26 (1.42
/7.48) 3.01 (0.92
/9.85)
the work of Gullo et al. [15] or Stein et al. [18] (the
Smoking status (cigarettes)
two studies that included the highest numbers of
Never 1Reference 1Reference
Former 1.26 (0.78
/2.04) 1.18 (0.57
/2.44) both cases and control subjects), our estimated
Current 2.06 (1.19
/3.57) 2.39 (1.14
/5.02) prevalence of about 13.4% for EPI in the 70
/75
ACE-inhibitor intake years age group would correspond to a true pre-
No 1Reference 1Reference valence of 12.9% or 8.2%, respectively after correc-
Yes 0.55 (0.31
/0.99) 0.23 (0.07
/0.77) tion for misclassification. Furthermore, a positive
Abbreviations: EPI/exocrine pancreatic insufficiency; SEPI/
and negative predictive value of 74.0% and 96.6% or
severe exocrine pancreatic insufficiency. 58.9% and 99.6%, respectively could be derived.
*All variables in the model controlled for each other; $EPI (B/200 The corrected prevalences are still much higher than
m g elastase
/1/g stool); %SEPI (B/100 m g elastase
/1/g stool). the aforementioned estimates of 1 to 2% in a
 Table VI. Test performance of faecal elastase-1 to determine exocrine pancreatic insufficiency (EPI) as described in various studies*.

702
Study population Comparison

D. Rothenbacher et al.
Authors [Ref.], country N (Gold standard) Results Comments

Amann et al. [13]
USA
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14 patients with CP (mild or moderate 7, Secretin-pancreozymin SE (mild or moderate) 43%, Very few subjects. Some
severe 7) test or ERCP or SE (severe) 100% controls suffer other
7 patients with non-pancreatic disorders leading pancreatic surgery SP 29% gastrointestinal disorders
to malabsorption
15 healthy controls

Dominguez-Munoz et al. [14] 20 patients with CP (mild 6, moderate or ERCP, ultrasonography, SE (mild) 0% Very few subjects. SE mild CP
Germany severe 14) CT SE (moderate/severe) 100% based on n/6
36 patients with non-pancreatic disease SP 83%
Gullo et al. [15] 44 patients with CP (mild 9, moderate 13, ERCP, ultrasonography, SE 77.3% Very good SP
Italy severe 22) medical history SE (severe/moderate) 91.4%
43 patients with non-pancreatic digestive disease SP 95.8%
53 healthy subjects
Hardt et al. [4] 210 patients with CP (mild 97, moderate 53, ERCP SE 45.3% Low SE for mild EPI Good SP
Germany severe 51) SP 75% for moderate and severe CP
12 patients without CP SE (moderate/severe) 57.4%
SP (moderate/severe) 86.4%
Lankisch et al. [16] 30 patients with EPI (mild 10, moderate or Secretin-pancreozymin SE 53% SE in mild CP low (based on
Germany severe 19) 30 patients without EPI test SE (severe) 82.7% n /10)
SP 94% Very good SP
Leodolter et al. [17] 33 patients with CP (mild or moderate 20, ERCP, ultrasonography, SE 50% Few subjects. SE in mild CP
Germany severe 13) CT SE (mild) 35%, lower
7 patients without CP SE (severe) 85%
SP 100%
Löser et al. [5] 26 patients with EPI (mild 13, severe 13) Secretin-caerulein test, SE 92.% Few subjects
Germany 25 patients with gastrointestinal disease ultrasonography, ERP SE (severe) 100% Good SP
SE (mild) 85%
SP 90%
Lüth et al. [3] 62 patients with EPI (mild 23, moderate 14, Secretin-caerulein test SE 84% SP in severe EPI better
Germany severe 25) SP 57%
65 patients without EPI SE (severe) 60%
SP (severe) 78%
Stein et al. [18] 63 patients with EPI Secretin-pancreozymin SE 96% SP 94% Very good SP
Germany 86 patients with cystic fibrosis test
Walkowiak et al. [19] 28 patients with cystic fibrosis Secretin-cholecystokinin SE 89.3% Very few subjects
Poland 55 children without gastrointestinal disease test SE (mild) 25%
SE (moderate/severe) 100%
SP 96.4%

Abbreviations: CP/chronic pancreatitis; ERCP/endoscopic retrograde cholangiopancreaticography, CT/computed tomography; SE/sensitivity; SP/specificity.
*Only studies with at least 30 subjects are considered.
 Exocrine pancreatic insufficiency among older adults
group of subjects aged 70 years. If the accuracy of
the test (as described in [15] and [18]) could be
corroborated in even larger validation studies, then
EPI may have been underestimated to some degree
by many other studies. Our results are supported by
the findings of two unselected autopsy studies which
suggested a prevalence of chronic pancreatitis of 6
/
12% [11,12].
Furthermore, we found a clear association of EPI
with age and a tentative higher prevalence of EPI in
men compared with women. This is in concordance
with previous reports [20]. In other, mainly clinical
reports, excessive alcohol consumption has been
reported as the main cause of chronic pancreatitis
[21,22]. In the current study, alcohol consumption
showed a U-shaped, non-monotonic relationship
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with prevalence of pancreatic insufficiency, with the
lowest prevalence of EPI in the group consuming less
than 60 g of ethanol per week. At higher levels of
alcohol consumption, prevalence was increasing
again. Since in the current study the number of
subjects consuming very high amounts of alcohol
was low, the association between very high amounts
of alcohol consumption and EPI or SEPI could not
be determined. A minimum of 6
/12 years of heavy
drinking ( /80 g ethanol per day) has been con-
sidered to be necessary for the development of
alcohol-induced chronic pancreatitis [22] which
would amount to /560 g ethanol per week. This
high consumption level was reported by less than
0.5% of the subjects in the current study and may
explain why we could not describe such an associa-
tion.
Clinical studies including patients with diabetes
also demonstrated that this patient group is espe-
cially prone EPI [23
/26]. We could only show that
patients with insulin-dependent diabetes had a
tendency towards the highest prevalence of EPI.
However, the number of patients with diabetes
included in our study was also quite small and
therefore we cannot draw firm conclusions regarding
this issue. This limitation may also be true for
patients with a history of gallstones or cholecystec-
omy; both factors have been described as relevant
factors for EPI in a clinical setting [27].
It has been suggested in several studies [21,28]
that smokers are at high risk for chronic pancreatitis.
Although cigarette smoking is often associated
with alcohol consumption and may be an impor-
tant confounding factor for the relationship bet-
ween alcohol and chronic pancreatitis, it is clearly
an independent risk factor for chronic pancreatitis
[28].
Years ago it was speculated that ACE inhibitors
may cause acute pancreatitis [29]. However, no
epidemiologic evidence had been presented so far,
703
and a recent retrospective cohort study in a large
group of elderly patients did not show an increased
risk for pancreatitis associated with ACE-inhibitor
intake [30]. Meanwhile, animal data showed that
ACE inhibitors alleviated chronic pancreatitis and
fibrosis and ACE inhibitors were suggested as
potential treatment for chronic pancreatitis [31].
Our data have delivered further evidence of the
potential beneficial effects of ACE inhibitors for
chronic pancreatitis in humans and suggest that the
anti-inflammatory effects of ACE inhibitors should
be investigated further as a potential component in
the treatment of chronic pancreatitis.
When looking on the results of the study the
following limitations have to be considered: as this
was a population-based study we had no invasive
means to determine chronic pancreatitis. However,
as demonstrated earlier, the faecal elastase-1 test
seems currently to be the best non-invasive test to
assess exocrine pancreas function with sufficiently
high sensitivity and specificity in the context of a
population-based study (the latter is of special
importance in preventing many false-positive re-
sults). Although our results may be overestimated
to some degree, the prevalence may be higher than
currently assumed.
Furthermore, we had to rely on stool samples that
were mailed to our study centre, which usually took
one day. However, this should not be a relevant
issue, as the faecal elastase-1 was found to be
stable and even the storing of stool samples for up
to 7 days at room temperature did not influence
the test performance [6]. The test is also unaffected
by previous gastrointestinal surgery or gastric dys-
motility [15], and medical conditions that could
impair test performance in clinical studies (such as
mucosal diseases of the small intestine or watery
diarrhoea) are of no or only minor relevance in this
study population because we used only solid stool
samples.
As is pertinent in a cross-sectional study design,
we cannot determine the time sequence of the
described associations and cannot distinguish cause
and effect with certainty. Therefore, these findings
should be corroborated in a longitudinal study
design.
Despite its limitations, we conclude that the
prevalence of EPI might be higher in the general
population than previously estimated. The preva-
lence increases with age and seems to be tentatively
higher in men than in women. However, smoking
seems to be an independent risk factor for and ACE-
inhibitor intake might be a protective factor of EPI
and SEPI. The latter finding may even point to new
options in the treatment of chronic pancreatitis.
 704 D. Rothenbacher et al.
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