Hereditary chronic pancreatitis

Abstract

Hereditary chronic pancreatitis (HCP) is a very rare form of early onset chronic pancreatitis. With the exception of the young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. As well, diagnostic criteria and treatment of HCP resemble that of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, most patients have a mild disease. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2), the serine protease inhibitor, Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) have been found to be associated with chronic pancreatitis (idiopathic and hereditary) as well. Genetic testing should only be performed in carefully selected patients by direct DNA sequencing and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. Pancreatic cancer risk is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.

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Orphanet Journal of Rare Diseases
Open Access
Review
Hereditary chronic pancreatitis
Jonas Rosendahl, Hans Bödeker, Joachim Mössner and Niels Teich*
Address: Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany
Email: Jonas Rosendahl - jonas.rosendahl@medizin.uni-leipzig.de; Hans Bödeker - hans.boedeker@medizin.uni-leipzig.de;
Joachim Mössner - joachim.mössner@medizin.uni-leipzig.de; Niels Teich* - niels.teich@medizin.uni-leipzig.de
* Corresponding author
Abstract
Hereditary chronic pancreatitis (HCP) is a very rare form of early onset chronic pancreatitis. With
the exception of the young age at diagnosis and a slower progression, the clinical course,
morphological features and laboratory findings of HCP do not differ from those of patients with
alcoholic chronic pancreatitis. As well, diagnostic criteria and treatment of HCP resemble that of
chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic
abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting,
maldigestion, diabetes, pseudocysts, bile duct and duodenal obstruction, and rarely pancreatic
cancer. Fortunately, most patients have a mild disease. Mutations in the PRSS1 gene, encoding
cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1
mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably
cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of
proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2), the serine
protease inhibitor, Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance
regulator (CFTR) have been found to be associated with chronic pancreatitis (idiopathic and
hereditary) as well. Genetic testing should only be performed in carefully selected patients by direct
DNA sequencing and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme
and nutritional supplementation, pain management, pancreatic diabetes, and local organ
complications, such as pseudocysts, bile duct or duodenal obstruction. The disease course and
prognosis of patients with HCP is unpredictable. Pancreatic cancer risk is elevated. Therefore, HCP
patients should strongly avoid environmental risk factors for pancreatic cancer.
Disease name/synonyms
Hereditary chronic pancreatitis
Definition/diagnostic criteria
Genetic definition
Already in 1952 Comfort and Steinberg were first to rec-
ognize that chronic pancreatitis may accumulate in
selected families suggesting a genetic background [1].
Thereafter, hereditary chronic pancreatitis (HCP) was
defined as an autosomal dominant disease with a pene-
trance of approximately 80%. However, in the daily clini-
cal setting the inheritance pattern cannot be determined
in some cases. In 1996 several groups mapped a gene for
HCP to chromosome 7 [2-4]. In the same year, Whitcomb
and colleagues identified an R122H mutation in the cati-
onic trypsinogen gene (PRSS1) [5]. Several other muta-
tions were described subsequently (A16V, D22G, K23R,
N29I, N29T, R122C) [6-12]. Until now, the R122H and
Published: 04 January 2007
Orphanet Journal of Rare Diseases 2007, 2:1 doi:10.1186/1750-1172-2-1
Received: 25 November 2006
Accepted: 04 January 2007
This article is available from: http://www.OJRD.com/content/2/1/1
© 2007 Rosendahl et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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N29I mutations of the PRSS1 gene have been identified as
the most common disease associated mutations [5-7].
In the last decade, several authors identified associations
of chronic pancreatitis (idiopathic and hereditary) to
other genes, such as the anionic trypsinogen (PRSS2), the
Serine Protease Inhibitor, Kazal type 1 (SPINK1) and the
cystic fibrosis transmembrane conductance regulator
(CFTR) [13-16]. On the other hand, environmental fac-
tors as smoking, alcohol consumption or the lack of anti-
oxidants were assumed to be important manifestation
factors, even in HCP [17-20] (Figure 1).
The definition of HCP as a classic autosomal dominant
disorder represents the current knowledge. However, the
criteria of the diagnosis of HCP have been changing over
the years and are currently different in the various clinical
centres. In the recently published Europac study, the diag-
nosis of hereditary pancreatitis was made on the basis of
two first-degree relatives or three or more second-degree
relatives, in two or more generations with recurrent acute
pancreatitis, and/or chronic pancreatitis for which there
were no precipitating factors. Cases in which these strict
criteria were not met, but more than one affected family
member was identified, mostly within the same genera-
tion, were classified as familial chronic pancreatitis [21].
However, the diagnostic value of this classification is
questionable. Therefore, we define HCP if the patient has
no other detectable cause of chronic pancreatitis and if he/
she has one first or second degree relative with proven
chronic pancreatitis. An international consensus is needed
in the near future to classify affected families unambigu-
ously.
Clinical definition and diagnostic criteria
Clinical definition
Chronic pancreatitis in adults is defined as a relapsing or
continuing inflammatory disease of the pancreas charac-
terized by irreversible morphological changes, upper
abdominal pain and, in some patients, permanent
impairment of exocrine function, endocrine function, or
both [22]. The clinical course during an acute attack may
range from mild edematous to severe necrotizing inflam-
mation of the pancreas. The resulting morphological
changes can be summarized as irregular sclerosis with
focal, segmental, or diffuse destruction of the paren-
chyma. Frequently dilatations, strictures, or intraductal
plugs can be seen in the pancreatic duct system. Initially,
chronic pancreatitis is characterized by a recurrent stage of
acute pancreatitis (early stage CP) passing over to progres-
sive pancreatic dysfunction and/or pancreatic calcification
(late stage CP).
Noteworthy in children the cardinal symptom is recur-
ring, suddenly appearing epigastric pain. Contrary to
adults, enduring pain is not a common clinical finding in
children. Other symptoms are nausea, vomiting and
abdominal pressure pain. Children partially develop pan-
creatic insufficiency with steatorrhoea and insulin-
dependent diabetes, but these complications normally
occur later than in patients with chronic alcoholic pancre-
atitis.
Diagnostic criteria
Diagnosis of chronic pancreatitis is made by clinical find-
ings, a typical medical and family history, imaging meth-
ods and pancreatic function tests. The use of invasive
function tests (secretin test, pancreozymin-secretin test) is
declining over the last years. In recent reviews it was stated
that invasive function tests in combination with pancre-
atic calcification are still the gold standard in the diagno-
sis of chronic pancreatitis, but these tests are laborious
and costly [23-26]. Non-invasive tests (faecal chymot-
rypsin, PABA-, pancreolauryl- and faecal elastase test) are
insufficient for the detection of minor or moderate insuf-
ficiency as a result of their restricted sensitivity compared
to the pancreozymin-secretin test. As a consequence, func-
tion tests are of restricted value, particularly in early stage
chronic pancreatitis [26,27]. A pragmatic and reasonable
treatment is the supplementation of pancreatic enzymes
ex juvantibus in patients with chronic pancreatitis and sus-
pected exocrine insufficiency.
So far no imaging test has been established for the diagno-
sis of early stage chronic pancreatitis. In patients with late
Diagrammatic illustration of genetic and environmental fac-tors with their suspected influence on the pathogenesis of chronic pancreatitisFigure 1
Diagrammatic illustration of genetic and environmental fac-
tors with their suspected influence on the pathogenesis of
chronic pancreatitis. Abbreviations: ACP = alcoholic chronic
pancreatitis, TCP = tropical calcific chronic pancreatitis, ICP
= idiopathic chronic pancreatitis, HCP = hereditary chronic
pancreatitis; abbreviations of the genes see within the text
(According to Witt, [85]).
ACP TCP ICP HCP
environmental factors genetic factors
environment genes
SPINK1 SPINK1 SPINK1 PRSS1
CFTR SPINK1
(PRSS1)
alcohol
smoking nutrition ? smoking
?
?
ACP TCP ICP HCP

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stage chronic pancreatitis several imaging methods
(ERCP, MR, MRCP, ES, CT, US, abdominal x-ray) are suf-
ficient to detect typical morphological changes (e.g. duct
alterations, calcification).
Epidemiology
There are no data regarding the incidence or prevalence of
chronic hereditary pancreatitis or of chronic pancreatitis
in children. The incidence of chronic pancreatitis of any
cause is expected to be about 3.5–10 per 100.000 inhabit-
ants and year in Europe and the USA [28,29].
Clinical description
Clinical characteristics
Alcoholic chronic pancreatitis and HCP exhibit essentially
identical clinical laboratory results and histopathological
or morphological features. Remarkably, HCP manifests
typically at an earlier age and pancreatic calcification and
diabetes mellitus are less frequent complications in com-
parison to chronic alcoholic pancreatitis. Certainly esti-
mable is the fact that most investigated subjects with the
N29I or R122H PRSS1 mutation had mild disease or were
asymptomatic [17,30].
Our investigations revealed no difference in the age of
onset between carriers of the these mutations. The median
age of onset was 11 years in the N29I and 10 years in the
R122H group, respectively. Only 4% of our patients had
severe chronic pancreatitis with exocrine and endocrine
insufficiency, pancreatic calcification and duct dilatation
as well as hospitalizations due to pancreatitis. In general,
half of the mutation carriers had little or no complaints or
complications [17]. A European study revealed a mean
age of onset of 10 years and 14.5 years for affected carriers
of the PRSS1 mutations R122H and N29I, respectively,
but showed no mutation-dependent differences in com-
plications such as exocrine or endocrine insufficiency or
increased pancreatic cancer risk [21]. Data on the frequen-
cies of acute pancreatitis attacks and pain in patients with
HCP are not available to date. Chronic pancreatitis
presents with a wide range of pain from mild to severe and
from intermittent to persistent. Interestingly, endocrine
insufficiency can regress over time, which is in contrast to
current believe, that pancreatic diabetes is an irreversible
sign of pancreatic failure [31]. However, prospective
investigations of the course of diabetes in patients with
HCP are lacking so far.
Hereditary chronic pancreatitis and pancreatic cancer
As shown in an investigation of 8 patients with pancreatic
cancer in a cohort of 246 HCP patients, the lifetime risk of
pancreatic cancer is about 50-fold higher than in the con-
trol population and corresponds with 1 per 1066 person-
years. It is only 20-fold elevated in patients with chronic
alcoholic pancreatitis [32,33]. In our cohort of 101 HCP
patients (25 N29I carrier, 76 R122H carrier), pancreatic
cancer was diagnosed in 3 patients with the R122H muta-
tion with a median of 23 years after the onset of pancrea-
titis. This corresponds to a rate of about 1 per 1200
person-years among affected R122H carriers [17]. Obvi-
ously, the data basis for the estimation of the pancreatic
cancer risk in patients with PRSS1 associated HCP is
small. The largest clinical investigation in the pre-genetic
era, however, revealed no pancreatic cancer in 72 patients
from 7 families [19]. Taken together, the pancreatic cancer
risk in HCP patients with a PRSS1 mutation seems to be
elevated – with an uncertain relative risk increase. Today,
there is no generally accepted protocol for screening HCP
patients for early pancreatic cancer. However, affected
mutation carriers should be strongly advised to stop
smoking, as it is an additional risk factor for pancreatic
cancer [34].
Other genes associated to chronic pancreatitis
SPINK1 mutations in chronic pancreatitis
Witt and colleagues described at first an association
between mutations of the serine protease inhibitor, Kazal
type 1 (SPINK1) and chronic pancreatitis [14]. SPINK1 is
a potent protease inhibitor thought to be a specific inacti-
vation factor of intrapancreatic trypsin activity. During
incubation of equimolar quantities of trypsin and SPINK1
the formation of a covalent bond between the catalytic
serine residue of trypsin and the lysine carboxyl group of
the reactive site of SPINK1 is carried out. After prolonged
incubation, trypsin activity reappears over time. This is
explainable by the fact that SPINK1 is degraded by trypsin
[35]. The most frequently found SPINK1 mutation is
N34S. This mutation was predominantly found in
patients with idiopathic chronic pancreatitis. Further
investigations showed an association of SPINK1 muta-
tions and alcoholic chronic pancreatitis as well as tropical
chronic pancreatitis [36-41]. Since 1–2% of controls carry
the N34S mutation, this mutation alone seems to be
insufficient to explain the pathogenesis of chronic pancre-
atits in mutation carriers. Moreover, a functional analysis
of recombinant SPINK1 with the N34S mutation showed
an unchanged function of N34S SPINK1 as well as an
unchanged trypsin susceptibility [42]. This indicates that
mechanisms other than the conformational change of
N34S might underlie the predisposition to chronic pan-
creatitis in mutation carriers.
CFTR mutations in chronic pancreatitis
Cystic fibrosis (OMIM 219700) is an autosomal recessive
disorder with an incidence in whites of approximately 1 in
2500 live births. In 1989, CFTR (OMIM 602421) was
identified as the underlying gene. In 1998, Sharer and col-
leagues and Cohn and colleagues were able to show an
association of CFTR mutations with chronic pancreatitis
[15,16]. This association is pathophysiologically compre-

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hensible since 1–2% of patients with cystic fibrosis suffer
from chronic pancreatitis [43,44]. The variety of pancre-
atic disorders in cystic fibrosis range from complete loss of
exocrine and endocrine function to almost normal pan-
creatic function. So far more than 1500 mutations of the
CFTR gene have been described [45]. According to their
effect the mutations are split up in five or six classes (I-V/
VI) [46,47]. In cystic fibrosis, the most common mutation
is F508del, accounting for approximately 66% of all
mutated alleles [48]. Interestingly, the clinical course of
cystic fibrosis can be variable in patients carrying the same
mutations, indicating the influence of environmental and
maybe other genetic factors.
Recently published studies confirmed the association of
chronic pancreatitis and CFTR mutations, but until now
the underlying mechanisms leading to the development
of chronic pancreatitis are poorly understood [49-54].
One of the main findings in all investigations is the detec-
tion of mostly rare CFTR mutations showing a different
spectrum of detected mutations than in cystic fibrosis and
congenital bilateral aplasia of the vas deferens (CBAVD).
Some authors state that compound heterozygous CFTR
carriers have a distinct elevated risk for the development
of chronic pancreatitis, which is even higher when an
additional SPINK1 mutation is present [51,54].
However, the role of some CFTR mutations has to be
reconsidered since Rohlfs et al. demonstrated that the
mutation I148T in Exon 4, which was classified as a severe
cystic fibrosis causing mutation, is not associated to cystic
fibrosis. According to their data the complex allele
3199del6 and I148T seems to be the relevant factor [55].
In summary, CFTR mutations alone are not sufficient for
the pathogenesis of chronic pancreatitis in most patients
and further studies are needed to elucidate the role of
CFTR in the pathogenesis of chronic pancreatitis.
PRSS2 mutations in chronic pancreatitis
In an actual study of 2466 patients with chronic pancrea-
titis (including 1857 with hereditary or idiopathic pancre-
atitis) and 6459 controls by Witt et al., the G191R variant
of the anionic trypsinogen was over represented in con-
trols (32 vs. 220, odds ratio 0.37; P = 1.1 × 10
-8
). The anal-
ysis of the recombinantly expressed G191R variant
revealed a complete loss of trypsin activity due to the
introduction of a novel tryptic cleavage site that renders
the enzyme hypersensitive to autocatalytic proteolysis.
Taken together, the G191R variant of PRSS2 mitigates
intrapancreatic trypsin activity and thereby plays a protec-
tive role against chronic pancreatitis [13]. This is the first
study demonstrating a mutation with a protective effect in
chronic pancreatitis.
Aetiology and biochemical analysis of disease associated
PRSS1 mutations
Classic HCP seems to follow an autosomal dominant
inheritance with incomplete penetrance and highly varia-
ble disease expression. As stated above the results of
research done within the last decade implicate a more
complex inheritance pattern.
The PRSS1 mutations are located in three clusters within
the trypsinogen sequence: in the TAP (trypsinogen activa-
tion peptide), in the N-terminal part of trypsin or in the
longest peptide segment not stabilized by disulfide bonds
between Cys64 and Cys139 (Figure 2).
Thus, all pancreatitis associated PRSS1 mutations discov-
ered to date seem to cluster in the N-terminal half of the
molecule encoded by exons 2 and 3. It is important to
note, however, that investigation of the PRSS1 gene in
patients with suspected genetically determined chronic
pancreatitis is restricted to these exons in most laborato-
ries and possible C-terminal mutations may have been
missed. The discovery of pancreatitis associated cationic
trypsinogen mutations in 1996 demonstrated that
trypsinogen plays a central role in the pathogenesis of
human pancreatitis. These mutations seem to disturb the
balance of proteases and their inhibitors within the pan-
creas leading to autodigestion of the organ (Figure 3).
The R122H and the N29I mutations are the most com-
mon PRSS1 mutations worldwide. They have been fre-
quently reported from Europe, North America and Asia
[56] and R122H was also recently found in a family of
Linear map of pancreatitis associated mutations within the primary structure of the human cationic trypsinogenFigure 2
Linear map of pancreatitis associated mutations within the
primary structure of the human cationic trypsinogen. The
amino-acid positions affected by the pancreatitis-associated
PRSS1 mutations are denoted by asterisks (*). The positions
of the most frequent N29I and R122H mutations are indi-
cated. The blue call-out demonstrates the sequence of the
trypsinogen activation peptide (TAP) and the mutations
found in this region. The highly conserved tetra-aspartate
motif in the activation peptide is underlined and bold.
N29I R122H
* * ** * ** * ** *** **** *
TAP
N-…-Ala-Pro-Phe-Asp-Asp-Asp-Asp
-Lys-…-C
A16V D19A D22G K23R

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Aboriginal descent in Australia [57]. Neither mutation
was detected in two hereditary pancreatitis families from
Brazil [58] and no hereditary pancreatitis cases have been
reported from Africa. Here we summarize the most impor-
tant genetic and biochemical data of the two common
HCP associated PRSS1 mutations N29I and R122H. These
data are more extensively discussed in an actual review by
our group [59].
R122H and increased trypsin stability
David Whitcomb proposed that the Arg122-Val123 auto-
lytic peptide bond in trypsin plays an important role in
the degradation of prematurely activated trypsin in the
pancreas. Destruction of this "failsafe mechanism" by the
R122H mutation would increase intrapancreatic trypsin
activity and disturb the protease-antiprotease equilibrium
and eventually provoke pancreatitis [5]. Biochemical evi-
dence supports the notion that Arg122 is important for
autolysis of trypsin and mutations of this amino-acid
result in increased trypsin stability [60-63]. A study using
cerulein-induced zymogen activation in isolated rat acini
demonstrated that autodegradation of trypsin mitigates
cathepsin B-mediated trypsinogen activation, suggesting
that a failsafe mechanism might be indeed operational in
the mammalian pancreas [64]. The Whitcomb model in
its original form has remained very popular over the years,
even though more detailed biochemical analysis indi-
cated that the R122H mutation results not only in
increased trypsin stability but also in increased zymogen
stability and increased autoactivation [62,63]. A weak
trypsin-inhibitory activity associated with the Arg122 site
is also lost in the R122H mutant [63]. Thus, the pleio-
tropic biochemical effect of R122H raises the possibility
that the pathogenic alteration is unrelated to trypsin sta-
Model of inherited pancreatitisFigure 3
Model of inherited pancreatitis. In the normal pancreas (left) trypsin that is prematurely activated within the pancreas is inhib-
ited by SPINK1 and in the second line by trypsin and mesotrypsin preventing autodigestion. In inherited pancreatitis (right)
mutations in PRSS1 or SPINK1 lead to an imbalance of proteases and their inhibitors resulting in autodigestion. The role of
CFTR is until now poorly understood. Abbreviations: AP = activation peptide (According to Witt, [85]).
? ?
Trypsin
Trypsinogen
Trypsin
AP
SPINK1
Trypsinogen
AP
Mesotrypsin
Trypsin
normal pancreas
inherited pancreatitis
enzyme cascade enzyme cascade
autodigestion autodigestion →
→→
→ pancreatitis
SPINK1
Mesotrypsin
Trypsin
CFTR CFTR

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bility. More importantly, the model fails to explain how
the other pancreatitis associated PRSS1 mutations might
work, as the majority of these do not affect trypsin stabil-
ity.
N29I and enhanced trypsinogen autoactivation
Biochemical characterization of the N29I mutation using
recombinant trypsinogen found no effect on trypsin or
trypsinogen stability. On the other hand, two independ-
ent laboratories observed moderately increased autoacti-
vation in 4 studies [62,65-67]. The N29T mutant, firstly
described by Pfützer et al. in 2002, exhibited a phenotype
similar to that of R122H, both increased trypsin stability
and enhanced autoactivation were documented [11,64].
Because increased autoactivation was observed with the
R122H, N29I and N29T mutations, whereas N29I had no
effect on trypsin stability, the logical conclusion was put
forth that enhanced autoactivation is the common patho-
genic mechanism of hereditary pancreatitis associated
PRSS1 mutations [62].
Animal models
Genetically engineered animals offer the opportunity to
study the effects of the foresaid mutations in vivo.
Transgenic expression of rat SPINK1 in mice reduced the
severity of experimental secretagogue-induced pancreati-
tis [68]. The transgenic animals had 190% increased
endogenous trypsin inhibition capacity. Transgenic
expression of SPINK1 did not hinder trypsinogen activa-
tion, but reduced trypsin activity after supramaximal stim-
ulation with cerulein. These in vivo results underline the
hypothesis that enhanced inhibitory capacity of trypsin
protects against pancreatitis.
Results from a mouse with targeted disruption of the pan-
creatic secretory trypsin inhibitor are puzzling [69]. A
knockout (-/-) of the mouse homologue of human
SPINK1, murine Spink3, is lethal within two weeks after
birth. Spink3 -/- embryos developed normally until day
15.5 after conception. Subsequently, autophagic degener-
ation of the pancreatic acinar cells started, interestingly
without significant inflammatory cell infiltration. In this
study, the authors were not able to detect enhanced
trypsin activity in the acinar cells of the SPINK -/- animals.
However, in a further study enhanced tryptic activity was
found in pancreatic acini prepared one day after birth
using a more sensitive assay [70]. Therefore, these data
indicate that the total loss of SPINK3 function leads to a
strong imbalance in favour of trypsin activity resulting in
acinar cell death and involution of the whole gland and
finally leading to the lethal phenotype.
Two recent publications describe transgenic animals
expressing R122H mutated trypsinogen [71,72]. Our
group developed a mouse expressing R122H human
trypsinogen in the exocrine pancreas by using the rat
elastase-2 promoter [71]. The animals showed slightly ele-
vated serum levels of lipase without any significant histo-
logical alteration, suggesting a subtle acinar damage. After
repetitive induction of experimental pancreatitis, pancre-
ata of transgenic animals showed a higher inflammatory
reaction than controls. The mild phenotype in these ani-
mals is probably caused by a low expression level of
R122H mutated trypsinogen.
Transgenic expression of the R122H mutation of murine
trypsin 4 in mouse pancreas led to progressive fibrosis and
chronic inflammation of the pancreas [72]. Repetitive
inductions of experimental pancreatitis with supramaxi-
mal doses of cerulein resulted in extensive deposition of
collagen in periacinar and perilobular spaces of the trans-
genic animals. Thus, this animal model, which gives a sig-
nificant expression level of R122H mutated trypsinogen,
seems to recapitulate the human disease.
In summary, the animal studies indicate that disarranging
the balance between trypsin and its inhibitors in favour of
a higher intra-acinar tryptic activity contributes to the
development of pancreatitis.
The trypsinogen und SPINK1 mutation database
Since the first description of a trypsinogen mutation in
hereditary pancreatitis, the experimental and clinical
information on genetic alterations in chronic pancreatitis
has been rapidly growing, resulting in a more and more
complex data set. To address this issue, we implemented a
continuously updated database in early 2001, which con-
tains all genetic variants of the PRSS and SPINK1 genes
[73]. In addition to exact genetic data, this database con-
tains links to the clinical characterization of patients with
different mutations and to in vitro studies with mutant
molecules.
Molecular diagnostic methods
The recommended "gold standard" method is direct DNA
sequencing of both strands. Most laboratories have
focused their studies on PRSS1 exons 2 and 3, and until
now no unambiguous disease associated mutation has
been identified in the other exons. However, it is still pos-
sible that new variants will be identified in exons 1, 4 and
5, or in the intronic and promoter regions. Interestingly,
the triplication of a segment containing the PRSS1 gene
was actually found in certain patients with HCP. This trip-
lication seems to result in a gain of trypsin through a gene
dosage effect and represents a previously unknown mech-
anism causing HCP [74].
There are several more methods to detect PRSS1 muta-
tions such as single strand conformation polymorphism

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analysis (SSCP), restriction fragment length polymor-
phism analysis (RFLP) or denaturing high performance
liquid chromatography (DHPLC). These methods are lim-
ited by a lack of sensitivity and specificity and since the
nucleotide sequence is not detected subsequent sequenc-
ing of the altered probe is necessary in most cases. Above
all Howes et al. showed that false negative results may be
obtained regarding the R122H mutation, if RFLP is used
with the restriction endonuclease Afl III, when a neutral
polymorphism is present within the restriction site [75].
Melting curve analysis using fluorescence resonance
energy transfer (FRET) probes is a highly efficient method
with a very high sensitivity and specificity, however, only
detecting the defined mutation and only partly other
mutations located under the probes.
Therefore, since DNA sequencing has become more
affordable within the last years and is also able to detect
further mutations within the amplified fragment,
sequencing of both strands should be performed.
Differential diagnosis
Well-recognized causative factors of chronic pancreatitis
are anatomic anomalies, metabolic disorders, trauma,
cystic fibrosis and inflammatory bowel disease. Since
HCP manifests predominantly in childhood or early
adulthood, alcohol abuse as the most common predispos-
ing condition can nearly be ruled out. One of the most
important differential diagnoses is cystic fibrosis. There-
fore, all patients with onset of the disease in childhood
and early adulthood should be screened for a pathological
sweat chloride test and subsequently for the most com-
mon CFTR mutations of their population. Other rare dif-
ferential diagnoses are hyperlipidaemia type I, familiar
(hypocalciuric) hypercalcaemia (FBH), hereditary hyper-
parathyroidism and autoimmune pancreatitis, last-men-
tioned usually manifesting in late adulthood [76-80].
Genetic counselling and testing
First of all, genetic counseling should be performed in an
experienced multi-disciplinary clinic that can address the
resulting issues. Before genetic testing is performed impli-
cations of finding HCP related mutations in the PRSS1
gene for the health and the medical care of the patients
should be discussed. Moreover, the elevated pancreatic
cancer risk and the possible adverse effects for the patient
regarding health and life insurance and employment
should be brought up. Before performing the test, the
form of communicating the test result should be assessed.
Genetic testing should only be performed after informed
consent.
The indication for PRSS1 and SPINK1 mutation testing in
symptomatic patients should be one of the following:
1. recurrent unexplained attacks of acute pancreatitis and
a positive family history
2. unexplained chronic pancreatitis and a positive family
history
3. unexplained chronic pancreatitis without a positive
family history after exclusion of
other causes (see differential diagnoses)
4. unexplained pancreatitis episode in children
Noteworthy, genetic testing in children is a complex issue,
since depending on their age children cannot always be
included in the process of decision making whether
genetic testing should be performed. Therefore, extensive
genetic counseling, illuminating the above-mentioned
aspects is necessary. Another important facet may be the
information for anxious parents that genetic testing can-
not predict the age of onset or the severity of the disease
and that the findings of the analysis do not change the
management of the disease today.
Beyond the hitherto discussed aspects the detection of
PRSS1 and SPINK1 mutations will lead to a correct classi-
fication of the disease, helping the affected individual to
better understand their disease and clearing out misclassi-
fications (e.g. alcoholic chronic pancreatitis).
Predictive genetic testing should only be offered by a rec-
ognized service with adequate pre-test counselling, post-
test support and clinical follow up. The persons capable of
testing should have a first degree relative with a defined
HCP gene mutation, should be able to understand the dif-
ferent above mentioned aspects and the request for
genetic testing should have been consistently stated [81].
We want to emphasize anew that all HCP patients or
potential PRSS1 mutation carriers should be informed
that the finding of a disease associated mutation does nei-
ther predict the onset or course of the disease nor affords
specific diagnostic or therapeutic consequences.
Antenatal diagnosis
As the penetrance of inherited PRSS1 mutations is incom-
plete, and a highly variable disease manifestation occurs
within the most families, no antenatal diagnosis should
be encouraged. Even in recently published guidelines con-
cerning genetic testing in HCP the authors had reserva-
tions against antenatal diagnosis, but highlight that they
cannot be so prescriptive as to refuse molecular genetic
testing in an age of patient autonomy and informed con-
sent [81]. Requesting parents should be informed, that
even a painful course of the disease is self-limited to only

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Page 8 of 10
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a few years in the most cases. No patient in our cohort find
his life not lifeable due to disease-associated health limi-
tations.
Management including treatment
No prospective randomised trial has been published for
any medical or surgical problem in the management of
HCP. Several case reports, but few systematic studies,
address the medical and surgical treatment of HCP. Gen-
erally, the treatment does not differ from common forms
of chronic pancreatitis.
In most instances treatment of chronic pancreatitis
focuses on pain management, maldigestion, diabetes,
pseudocysts, bile duct obstruction, duodenal obstruction
and pancreatic cancer [27,82-84]. Regarding pain man-
agement amenable causes like pseudocysts, biliary and
duodenal obstruction, and coincident peptic ulceration
should be ruled out before an adequate pain therapy is
started.
To stop the progression of the disease the consumption of
alcohol should be an infrequent event, whereas smoking
should be avoided completely. In concern of pancreatic
insufficiency, frequent small meals with a low fat content
may help to limit pancreatic stimulation while maintain-
ing caloric intake. Maldigestion should be treated by sup-
plementation of pancreatic enzymes in sufficient dosage.
Management of endocrine failure is carried out according
to the guidelines of approved diabetes societies.
A widely accepted indication for surgery in patients with
HCP is chronic pain in the presence of a persistent dilata-
tion of the main pancreatic duct. Many surgeons favour a
longitudinal pancreaticojejunostomy (Puestow procedure
modified by Partington and Rochelle) with good early
results.
However, in patients without pancreatic duct dilatation,
the operation seems not to be beneficial for the further
course of pancreatitis or for the quality of life [85]. In
addition, surgical interventions should be discussed with
caution in children, as periods of only a few or even no
symptoms frequently extend into adulthood. For these
reasons, a decision to wait and see might be more appro-
priate than early operation in paediatric patients with
HCP. In adults, surgical decisions on the basis of the
guidelines concerning the indications for surgical treat-
ment of patients with chronic pancreatitis of the more
common underlying causes seem to be as effective in
patients with HCP as in patients with chronic pancreatitis
of other origins [86]. Unfortunately, there are no data
regarding endoscopic procedures in the management of
chronic pancreatitis patients. Therefore, prospective stud-
ies are needed to further elucidate the role of surgical and
endoscopic management in chronic pancreatitis.
Prognosis
Today, the individual prognosis of HCP is unpredictable.
It is neither possible to predict further episodes of acute
pancreatitis, chronic bile duct obstruction, exocrine or
endocrine pancreatic insufficiency nor the individual risk
of pancreatic cancer.
Unresolved questions
From a genetic aspect, a more interesting quest in the near
future will be for modifier genes that might explain the
incomplete penetrance i.e. why some carriers of PRSS1
mutations remain healthy, whereas their relatives with the
same mutation exhibit severe disease. Despite intensive
research, the disease mechanism remains poorly under-
stood. The biochemical alterations caused by the muta-
tions have been mostly clarified in vitro, but their
phenotypic effect in vivo in most instances remains
unclear. In this respect, future development of cellular
and animal models of HCP will be particularly valuable.
Competing interests
The author(s) declare that they have no competing inter-
ests.
Note
Some parts of this work have been published in "Human
Mutation" [59].
Acknowledgements
We gratefully acknowledge the helpful discussion with Professor Miklos
Sahin-Tóth/Boston.
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