Chronic Pancreatitis: A Changing Etiology

Raffaele Pezzilli
1
, Andrea Lioce
1
, Luca Frulloni
2
1
Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital. Bologna, Italy.
2
Department of Biomedical and Surgical Sciences, University of Verona. Verona, Italy
Introduction
In 1998, Lankisch and Banks reported that the
prevalence of chronic pancreatitis appeared to
be in the range of 3-10 per 100,000 people in
many parts of the world [1]. They also
emphasized that the most important medical
problems associated with the disease included
abdominal pain, steatorrhea, diabetes mellitus
and the possibility that chronic pancreatitis
may be considered a premalignant condition
[2, 3]. In 2002, in a well-written review,
Banks pointed out that the two important
forms were alcoholic and tropical pancreatitis
[4].
There is no doubt that that, in Western
countries, alcohol is the most frequent
associated factor of chronic pancreatitis, that
alcoholic chronic pancreatitis presents
clinically in young adults of 30-40 years of
age, with a higher prevalence of the male
gender, that the histological lesions are
chronic “ab initio” and that, from a clinical
point of view, the disease is characterized by
recurrent attacks of abdominal pain. In
Western countries, in the period from 1940 to
2003, alcohol frequency increased as an
etiological factor of chronic pancreatitis from
19 [5] to 50% [6] and even up to 80% [7, 8].
The results of the latter study regarding the
etiology of chronic pancreatitis were
subsequently confirmed by others in Europe
[9, 10, 11, 12, 13, 14, 15, 16] as well as in
Brazil [17], Australia [18] and South Africa
[19]. On the other hand, four consecutive
surveys carried out in Japan (from 1979 to
1977, from 1978 to 1984, in 1994, and in
1999, respectively) [20] showed that alcohol
as an etiological factor accounted for fewer
than 60% of the cases of chronic pancreatitis
in this country. The study of Sarles et al. [8]
reported that India is the most characteristic
country in which patients with chronic
pancreatitis were mainly malnourished in
childhood, assuming a low fat and low protein
diet; they were also not alcoholics. Thus, this
particular form of the disease was named
“tropical pancreatitis”. Subsequent studies
from India and Africa confirmed this finding
as was reported in the review article published
by Mohan et al. in 2003 [21].
The Importance of the Etiology
From a practical point of view, understanding
the pathogenesis may lead to the
identification of novel molecular targets and
the development of new potential therapeutic
agents. Thus, the role of alcohol is the
cornerstone of the pathogenesis of chronic
pancreatitis, at least in Western countries.
Durbec and Sarles [7] clearly demonstrated
that alcohol is a risk factor for chronic
pancreatitis; in fact, they showed that the
relative risk would be multiplied
approximately by a factor of 1.4 when passing
from one 20-gram intake to the next.
Furthermore, the increase appears to be more
rapid when passing from the class of non-
drinkers to that of 20-gram of alcohol intake
per day. The mechanism which determines
the main manifestation of chronic
pancreatitis, i.e., fibrosis of the pancreatic

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gland, has been well-summarized by Taludkar
et al. [22]. In brief, the oxidation of ethanol to
acetaldehyde determines the activation of the
pancreatic stellate cells in the quiescent state
without any pre-activation; this process
generates a state of oxidant stress within the
pancreatic stellate cells which subsequently
activates the downstream pathways of the
fibrogenesis. This finding implies that, in the
human pancreas, pancreatic stellate cells may
be stimulated early during chronic alcohol
intake even in the absence of necro-
inflammation. The importance of the
oxidative stress in chronic pancreatitis
patients has also been reported using breath
analysis [23]. Regarding tropical pancreatitis,
several hypotheses have been made, in
particular, the malnutrition theory, the cassava
hypothesis and the oxidant stress hypothesis
[21]. Thus, also in this particular form of the
disease, it is possible that there is activation
by certain substances of the pancreatic stellate
cells.
However, according to this postulated
pathogenesis, alcohol seems to induce
pancreatic fibrosis as has frequently been
found in autoptic series of alcoholics without
clinical history of chronic pancreatitis [24, 25,
26].
Furthermore, animal models of alcoholic
chronic pancreatitis have not been able to
induce pancreatic damage similar to that
observed in human chronic pancreatitis;
alcohol requires prior sensitization with other
agents (viruses, obstruction) in order to
produce damage similar to that found in
humans.
In summary, alcohol represents a defined risk
factor for chronic pancreatitis; it is capable of
inducing pancreatic fibrosis by its action on
the pancreatic stellate cells, but its role in the
etiopathogenesis of the disease is still being
debated.
New Advances in Etiology
Genetic Factors
The possibility of evaluating the mutations of
the
cystic
fibrosis
transmembrane
conductance regulator-gene (CFTR-gene)
[27], as well as the discoveries of mutations
of cationic trypsinogen gene (protease-serine-
1 gene, PRSS-1) [28] and serine protease
inhibitor, Kazal type 1 gene (SPINK-1) [29],
has led to better evaluating the
familial/hereditary forms as well as idiopathic
forms of chronic pancreatitis in Western
countries. In tropical pancreatitis it has also
been noted that this disease has been highly
associated with the SPINK-1 N34S mutation
[30, 31] whereas the frequency of CFTR
mutations was lower than in white subjects
[32]. The PRSS1 mutations appear capable of
inducing chronic pancreatitis whereas CFTR
and SPINK-1 seem to be “gene modifiers”
capable of inducing the disease in the
presence of a risk factor such as alcohol [31,
33].
Autoimmune Diseases
In 1961, Sarles et al. [34] reported the case of
a non-drinker suffering from pancreatitis
associated with hypergammaglobulinemia.
The authors hypothesized that the disease in
this patient was an autonomous pancreatic
disease of autoimmune origin. After this
report, other authors around the world
described similar cases. In 1995, Yoshida et
al. [35] suggested the term “autoimmune
pancreatitis” for this disease and, therefore,
this term has become largely accepted for
pancreatic disease of an autoimmune origin.
In the past 10 years, an increasing number of
cases have been reported in all countries [36]
and the frequency of autoimmune pancreatitis
will probably increase in the next few years.
Changing Lifestyle
The impact of changing lifestyle, especially in
developing countries, may contribute to
modifying the etiology of chronic
pancreatitis. For example, alcohol
consumption in developing countries may
increase [37] and this could change the
etiology of chronic pancreatitis in those
countries. On the contrary, in Europe, there
was a progressive reduction of alcohol
consumption from 1961 to 1991 [38].
Furthermore, taking into account the lifestyle
of chronic pancreatitis patients, it has been

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reported that the pancreatic functional
changes caused by alcoholic pancreatitis
progress even after cessation of alcohol use,
but the progression is slower and less severe
when alcohol intake is stopped [39].
The Frequency of Change in Etiology
All these new factors and changing lifestyle
may contribute to changing the frequencies of
the various etiologies of chronic pancreatitis.
This is the reason why, from 2004 to the
present, the etiological features of chronic
pancreatitis have been reported to be different
than in the past. Four studies are examples of
this. In Korea [40], the main etiological factor
remains alcohol (64.3%) followed by an
unknown etiology (20.8%), obstruction
(8.6%) and autoimmune pancreatitis (2.0%).
In a recent survey on chronic pancreatitis in
the Asian-Pacific region [41] there was a
great variability in the frequency of alcoholic
pancreatitis, accounting for about 19% of
chronic pancreatitis cases in China to 95% in
Australia whereas tropical pancreatitis was
46.4% in China and, obviously, was not
present in Australia. In a recent survey of
chronic pancreatitis in Italy [42], chronic
pancreatitis associated with alcohol abuse
accounted for less than 50% of cases and this
figure is lower than that reported by Gullo et
al. in 1977 [9]. However, some regional
differences regarding the frequency of
alcoholic chronic pancreatitis exist in Italy. In
fact, in Bologna (located in Northern Italy),
alcohol as an etiological factor remains high
(80.4%) [43] whereas, in Sicily (located in the
Southern Italy), the percentage of alcoholic
chronic pancreatitis is about 60% [44]. In a
survey of chronic pancreatitis in Italy [42],
alcohol as an etiological factor of chronic
pancreatitis is followed by obstruction (27%),
pancreatitis of unknown origin (17%),
autoimmunity (4%) and hereditary/genetic
factors (4%). The most surprising results
come from India. In a prospective nationwide
study in India [45], the authors found that the
majority of patients had pancreatitis of
unknown origin (60% of the cases); alcoholic
chronic pancreatitis accounted for a third of
the cases whereas tropical pancreatitis was
present in only 3.8% of the cases. It seems
that alcohol tends to be increasing in
frequency in India as is chronic pancreatitis of
unknown etiology. However, the data
reported by the Indian researchers (60% were
idiopathic forms of chronic pancreatitis) need
to be better re-evaluated. In this regard, it is
worth noting that the frequency of unknown
origin chronic pancreatitis is 17% in the
Italian survey [42] ranging from about 12% in
Bologna to 38% in Sicily [43, 44].
Conclusions
The evidence of recent surveys on chronic
pancreatitis carried out around the world
shows that alcohol remains the main factor
associated with chronic pancreatitis, even if at
a frequency lower than that reported in the
past. Autoimmune pancreatitis accounts for 2-
4% of all forms of chronic pancreatitis, but
this frequency will probably increase over the
next few years. The rise of idiopathic chronic
pancreatitis, especially in India, represents a
black hole in recently published surveys.
Despite the progress made so far regarding
the possibility of establishing the hereditary
forms of chronic pancreatitis and the
recognition of autoimmune pancreatitis, is it
possible that we are more inaccurate today
than in the past in identifying the factors
associated with chronic pancreatitis in our
patients?
Keywords Cohort Studies; Combined
Modality Therapy; Data Collection; Genetics,
Pancreatitis, Alcoholic; Pancreatitis, Chronic;
Population
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
Raffaele Pezzilli
Department of Digestive Diseases and
Internal Medicine
Sant’Orsola-Malpighi Hospital
Via Massarenti, 9
40138 Bologna
Italy
Phone: +39-051.636.4148

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591
 
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