4th
Joint Meeting of Italian-Hungarian Pancreatologists
Capri (Italy). September 30th, 2000
JOP. J Pancreas
(Online) 2000; 1(3 Suppl.):69-76.
Gastroenterological
and Surgical Department, Policlinico "GB
Rossi", University of Verona. Verona, Italy
Relationship
Between Chronic and Acute Pancreatitis
The aetiology of pancreatitis is still partly uncharted
territory, and whether it originates in the acinar
cells or from a disease of the pancreatic ducts continues to be a debatable
issue [1]. For this reason, it still proves impossible to establish a definite
relationship between acute (AP) and chronic pancreatitis (CP), in that the
basic question as to whether or not these are two distinct diseases in physiopathological terms has still to be answered. In
recent years, however, substantial progress has been made and important
insights have been gained, particularly with regard to certain types of
pancreatitis.
Taking
clinical observations as our starting point in this review, we sometimes see
that major acute exacerbation occurs in the course of CP taking the form of
severe AP. In a very limited number of cases, moreover, CP manifests itself
initially as a severe episode of AP. It has long been recognized that severe
acute exacerbation is part of the clinical picture of CP [2]. In our
experience, roughly 18% (153/853 cases) of CP sufferers have experienced an
episode of severe acute pancreatitis in the course of the disease; fewer than
half of these patients (70/853 = 8.2%) experienced such episodes at the onset
of CP. Only 8 (9%) of the patients with severe AP at the onset of CP were
easily identifiable as chronic cases, presenting, for instance, intraductal calcifications. The real problem, then, arises
when the episode of AP of non-biliary origin occurs without any Wirsung duct abnormalities suggestive of CP. In this
situation, even today, the correct diagnosis can often be achieved only as a
result of follow-up of the patient.
In the
literature, the relationship between an episode of AP and the existence of CP
has been the subject of several studies over the years which have sought to
postulate possible pathogenetic mechanisms.
The first
hypothesis is that the AP episode, if associated with a high alcohol intake, is
very often, in actual fact, the first manifestation of CP; as we have already
said, the pancreas sometimes presents typical morphological characteristics
such as Wirsung duct abnormalities or calcifications
[3, 4, 5].
There is a
second hypothesis. Whereas restoration of integrity is the norm in cases of
edematous AP [6], healing in necrotizing AP may be imperfect with the formation
of scars which give rise to stenosis, for example, of the main duct, thus
causing obstructive-type CP. This may also occur in the case of formation of pseudocysts, more often in the head of the pancreas [7],
due to AP and Wirsung duct rupture [8, 9]. If the
stenosis of the main duct is in the head, then, of course, most of the
pancreatic ducts will be affected by the obstruction. Sometimes the obstruction
is in the body of the gland, with the result that distinct abnormalities of the
main duct are observed in the body and tail, whereas the head portion presents
normal morphological characteristics. Sarles et
al. believe that the only way that AP can progress to CP is essentially via
fibrotic-cicatricial stenosis of the ducts which may
occur as a result of the acute episode [10]. In effect, evidence has been found
to show that AP does not always heal without abnormalities of the main duct,
though the latter usually tend to be fairly mild in nature [11, 12]. In the
past it often happened that the obstructive origin of chronic pancreatitis with
involvement of Wirsung's duct was neither recognized
nor treated; in such cases, with the passing of time and the subsequent
occurrence of lesions, the endoscopic retrograde cholangiopancreatography
findings revealed morphological changes progressing from a state of homogeneous
dilatation of the duct above the stenosis to major irregularities with
calcifications [13], and ultimately leading, after many years of disease, to a
condition which can hardly be distinguished from CP of non-obstructive origin.
There is no doubt that alcohol may have an impact on this process; in
experiments in mongrel dogs, alcohol intake in the presence of Wirsung duct obstruction aggravated what would otherwise
have been a mild CP [14].
A third
possibility is that repeated episodes of AP may lead to CP [15]. Support is
lent to this hypothesis above all by morphological studies conducted by Klöppel who believes that the changes occurring in CP stem
initially from an AP according to a necrosis-fibrosis sequence. As he sees it,
AP characterised by peripancreatic
necrosis does not develop into CP, whereas intrapancreatic
necrosis may cause perilobular fibrosis and
interlobular duct distortion with resulting stenosis of the ducts and a classic
picture of CP [16, 17]; the stenosis is then thought to be responsible for the
difficult outflow of pancreatic secretions with protein precipitation and
subsequent calcification. This hypothesis is at variance with that of the 1963 Marseilles
classification in which AP and CP are two distinct entities caused by different
aetiological factors and in which it is postulated
that the lesion responsible for CP originates within the pancreatic duct [1, 2,
10].
Other
possible pathogenetic mechanisms, however, may be
involved. In rats, for instance, the role of ischaemia
induced by microvascular hyperfusion in AP would
appear to be associated with the subsequent development of anatomico-pathological
abnormalities characteristic of CP [18].
A major
contribution to explaining the relationship between AP and CP has recently been
made by the discovery that genetic abnormalities underlie some forms of
pancreatitis. In particular, in hereditary pancreatitis, an autosomal dominant
disease, mutations have been identified in the trypsinogen
gene: this makes prematurely activated trypsin resistant to inactivation
through autolysis [19]. Hereditary pancreatitis is characterised
by repeated attacks of AP which set in mainly in infancy [20], but also at a later
age, and then go on to develop into CP characterized by the usual picture of
calcifications, ductal distortion, fibrosis, exocrine pancreatic insufficiency
and diabetes [21, 22, 23, 24]. Hereditary pancreatitis appears to represent a
practically ideal model of how several episodes of AP can lead to CP. Perhaps
in non-hereditary AP, too, one of the first steps in the development of CP is
activation of trypsinogen at the intrapancreatic
level [25]. According to Whitcomb, the comparison between hereditary and
non-hereditary AP can be further extended by postulating the following process:
an initial episode of what he calls "sentinel" AP attracts monocytes
to the pancreas which become resident macrophages. These, in turn, cause
infiltration, differentiation and/or proliferation of pancreatic stellate
cells; these latter cells produce collagen if stimulated by transforming growth
factor beta (TGF-beta) produced by the macrophages in response to inflammation.
At this point, deposition of collagen leads to fibrosis and ultimately to CP
[25].
As far as
the aetiology of AP is concerned, cases of biliary
origin would not appear to progress to CP, unless obstruction (Oddi's sphincter or Wirsung duct
stenosis) is present [26], whereas, despite the considerations outlined here
above, AP in alcohol abusers sometimes does not develop into CP [5, 27]. If the
AP is associated with alcohol abuse, the patient may, for psychological reasons
due to the severity of the acute episode, stop drinking and sometimes even stop
smoking, as observed also in our experience [5]. Abstaining from alcohol in a
very early phase of CP may possibly modify the course of the disease; arrest of
the progression of pancreatographically detected main
duct abnormalities has, in fact, recently been documented after abstaining from
alcohol in patients with a suspected initial CP [28]. In addition, it should be
stressed that in most studies no account has been taken of cigarette smoking,
which would appear to play a more important role than was previously believed
in the pathogenesis [29] and evolution [30] of CP; In our own series, in fact,
it is fairly rare for a non-smoker to develop CP [31].
Therefore,
despite the difficulty of access to the pancreas for experimental observations
in man and the shortage of animal models, we can conclude that an association
exists between these two pancreatic diseases, though there may be different physiopathological explanations of this link, involving, in
all probability, several pathogenetic mechanisms.
Relationship
Between Chronic Pancreatitis and Pancreatic Cancer
Pancreatic
cancer as a cause of chronic pancreatitis
It should
be stressed right from the outset that pancreatic cancer is capable of causing obstruction
of the ducts giving rise to secondary CP which is well documented in anatomico-pathological terms [32, 33, 34]. The presenting
symptoms of pancreatic cancer at the onset may mimic those of CP [35] and it is
for this reason that, in all studies investigating the risk of pancreatic
cancer in the course of CP, those cases in which pancreatic cancer was
diagnosed shortly after a diagnosis of CP have always been excluded [36, 37,
38, 39]. In actual fact, the association between pancreatic cancer and CP is
relatively rare, estimates indicating that only approximately 5% of all
pancreatic cancer arise in patients who have been suffering from CP for lengthy
periods [36, 38, 40].
In our
experience, pancreatic cancer may have been misdiagnosed in approximately 1% of
our CP diagnoses [41]. This means that approximately one-third of all
pancreatic cancer diagnoses after a diagnosis of CP are likely to be late
diagnoses of tumour.
Furthermore,
not only pancreatic cancer, but also pancreatic intraductal
tumours may manifest with symptoms and, even more
importantly, imaging appearances which are fairly similar to, and can easily be
mistaken for those of CP. In particular, if the intraductal
tumour affects the ducts of the head of the pancreas,
a picture of chronic obstructive pancreatitis above the tumour
is possible, due to, amongst other things, the high viscosity of the pancreatic
secretions; if such tumours are not detected and
treated, they are likely to degenerate into invasive cancer [42, 43, 44].
Chronic
pancreatitis as a cause of pancreatic cancer
In many
diseases characterised by chronic inflammation (e.g.
chronic gastritis, ulcerative rectocolitis, Crohn's disease, Barrett's oesophagus,
etc.), there is an increased risk of cancer of the organ affected. The cause is
most probably related to the increased cell turnover and/or damage to the
genome induced by the inflammation [45]. This would also appear to be true of
CP, which various studies have now shown to be associated with an increased
risk of pancreatic cancer.
The first
report of an increased incidence of pancreatic cancer in the course of CP was
by Rocca et al. in 1987 [46]. After a debate lasting several years, the
present estimate of the risk in the Western population is based on the
multicenter study by Lowenfels et al. [38]:
approximately 4% of patients with CP develop pancreatic cancer within 20 years
of the onset of the disease, i.e. at a rate which is 15- to 16-fold greater
than that of the general population. As far as the Italian population is
concerned, the estimated increased risk is approximately 13.3-fold greater than
that of the general population [39]. In all the cohort studies conducted to
date [39, 46, 47, 48, 49, 50, 51, 52, 53], this finding has invariably been
confirmed with fairly similar values ranging from a minimum of 0.8% as reported
by Levy et al. [49] to the 8.3% figure reported by Augustine et al.
[50]. Studies of the case-control type, despite being far less reliable in this
field owing to the greater number of sources of potential bias they are subject
to, have substantially confirmed this association [36, 40]; the studies by Ekbom et al. [37] and the subsequent extension by Karlson et al. [54], present quite different values
[55]. In the more recent of the two studies, in fact, early detection of
pancreatic cancer is frequent (Standardized Incidence Ratio 22.2; Confidence
Interval 16.2-29.6), whereas there appears to be little or no increase 10 years
after diagnosis of CP (Standardised Incidence Ratio
2.2; Confidence Interval 0.9-4.4).
The aetiology of CP is a factor conditioning the risk of
pancreatic cancer. In tropical-type CP, whose pathogenesis is still undefined
but is probably related to undernutrition, the risk
of pancreatic cancer is much higher, affecting 8.3% of patients [50] with a
roughly 100-fold increased incidence compared to the general population [53].
In this latter study, the incidence is still very high even when excluding
patients with no histological diagnosis of pancreatic cancer. In hereditary CP
the risk is exceptionally high: approximately 40% of patients develop
pancreatic cancer by 70 years of age [56]. This finding is probably accounted
for by the early age of onset of hereditary CP, which gives rise to a lengthy
duration of the disease and to a proportional increase in the risk of
neoplastic degeneration.
Up until
only a few years ago, cystic fibrosis, an autosomal recessive disease which has
recently been shown to be associated with CP [57, 58], offered only a short
life expectancy. In recent years, as a result of improvements in knowledge of
the disease and in therapeutic methods, the life expectancy has risen
considerably and may now be as much as 50 years in subjects with limited
manifestations of the disease. An increased risk of pancreatic cancer has also
been found in cystic fibrosis [59, 60]. Since no increase has been observed in extrapancreatic tumours, the risk
must be regarded as organ-specific.
Western-type CP is associated with
alcohol intake in 75% of the cases. In those cases where smoking data are
reported, a strong association with cigarette smoking has also been noted as a
risk factor for the development of the disease [29, 61, 62, 63]. In our region
of Italy, approximately 90% of CP cases are heavy smokers and 80% of cases are
both heavy smokers and drinkers, whereas combined smoking and drinking is
present in no more than 16% of the general male population [31]. Among the
various risk factors for pancreatic cancer, the only major factor, apart from
black race [64] and exposure to certain chemicals [65, 66], is cigarette
smoking; alcohol, in fact, is not a risk factor for pancreatic cancer in the
vast majority of studies conducted [66, 67, 68]. Since both smoking and
inflammation can cause the onset of pancreatic cancer various studies have
failed to assess their relative incidence [36, 37, 38, 56]. Assessing
simultaneously the smoking habits of the general population and of patients
with pancreatic cancer and CP from the same geographical area in comparable
years, we evaluated the risk of pancreatic cancer associated with smoking
alone: approximately one-third of all tumours arising
in the course of CP are attributable to cigarette smoking, whereas the
remaining two-thirds are due to other factors such as chronic inflammation or
to other factors operating in combination with smoking [69]. The cancer risk,
on the other hand, would appear to be low and comparable to that of the general
population in non-smokers and ex-smokers; none of the 82 CP patients who
stopped smoking after onset of CP has yet developed a cancer after 12 years of
follow-up [39]. It may be important to advise CP patients, particularly those
who are still fairly young, to stop smoking, since this may have a major
preventive impact, though our findings are as yet insufficient to allow any
precise quantitative assessment of the benefit it affords.
Key
words Adenocarcinoma;
Alcohol Drinking; Carcinogens; Cystic Fibrosis; Diagnosis, Differential;
Epidemiology; Genetics; Incidence; Neoplasms; Risk Factors; Smoking
Abbreviations AP: acute pancreatitis; CP: chronic
pancreatitis; TGF: transforming growth factor
Correspondence
Giorgio Talamini
Digestive Endoscopy Service
Policlinico "GB Rossi"
University of Verona
37134 Verona
Italy
Phone: +39-045-807.4501
Fax: +39-045-508.815
E-mail address: talamini@borgoroma.univr.it
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