Chronic Pancreatitis: A Changing Etiology

Raffaele Pezzilli
, Andrea Lioce
, Luca Frulloni
Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital. Bologna, Italy.
Department of Biomedical and Surgical Sciences, University of Verona. Verona, Italy
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
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
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,
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
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
New Advances in Etiology
Genetic Factors
The possibility of evaluating the mutations of
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,
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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JOP. Journal of the Pancreas - - Vol. 9, No. 5 - September 2008. [ISSN 1590-8577]
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].
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
Keywords Cohort Studies; Combined
Modality Therapy; Data Collection; Genetics,
Pancreatitis, Alcoholic; Pancreatitis, Chronic;
Conflict of interest The authors have no
potential conflicts of interest
Raffaele Pezzilli
Department of Digestive Diseases and
Internal Medicine
Sant’Orsola-Malpighi Hospital
Via Massarenti, 9
40138 Bologna
Phone: +39-051.636.4148

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JOP. Journal of the Pancreas - - Vol. 9, No. 5 - September 2008. [ISSN 1590-8577]
1. Lankisch PG, Banks PA. Pancreatitis. New York:
Springer; 1998.
2. Lowenfels AB, Maisonneuve P, Cavallini G,
Ammann RW, Lankisch PG, Andersen JR, et al.
Pancreatitis and the risk of pancreatic cancer.
International Pancreatitis Study Group. N Engl J Med
1993; 328:1433-7. [PMID 8479461]
3. Lowenfels AB, Maisonneuve P, DiMagno EP,
Elitsur Y, Gates LK Jr, Perrault J, Whitcomb DC.
Hereditary pancreatitis and the risk of pancreatic
cancer. International Hereditary Pancreatitis Study
Group. J Natl Cancer Inst 1997; 89:442-6. [PMID
4. Banks PA. Epidemiology, natural history, and
predictors of disease outcome in acute and chronic
pancreatitis. Gastrointest Endosc 2002; 56(6
Suppl):S226-30. [PMID 12447272]
5. O'Sullivan JN, Nobrega FT, Morlock CG, Brown
AL Jr, Bartholomew LG. Acute and chronic
pancreatitis in Rochester, Minnesota, 1940 to 1969.
Gastroenterology 1972; 62:373-9. [PMID 5011528]
6. James O, Agnew JE, Bouchier IA. Chronic
pancreatitis in England: a changing picture? Br Med J
1974; 2:34-8. [PMID 4821040]
7. Durbec JP, Sarles H. Multicenter survey of the
etiology of pancreatic diseases. Relationship between
the relative risk of developing chronic pancreatitis and
alcohol, protein and lipid consumption. Digestion
1978; 18:337-50. [PMID 750261]
8. Sarles H, Cros RC, Bidart JM. A multicenter
inquiry into the etiology of pancreatic diseases.
Digestion 1979; 19:110-25. [PMID 478188]
9. Gullo L, Costa PL, Labò G. Chronic pancreatitis in
Italy. Aetiological, clinical and histological
observations based on 253 cases. Rendic Gastroenterol
1977; 9:97-104.
10. Thorsgaard Pedersen N, Nyboe Andersen B,
Pedersen G, Worning H. Chronic pancreatitis in
Copenhagen. A retrospective study of 64 consecutive
patients. Scand J Gastroenterol 1982; 17:925-31.
[PMID 7156887]
11. Ammann RW, Akovbiantz A, Largiader F,
Schueler G. Course and outcome of chronic
pancreatitis. Longitudinal study of a mixed medical-
surgical series of 245 patients. Gastroenterology 1984;
86:820-8. [PMID 6706066]
12. Dzieniszewski J, Jarosz M, Ciok J. Chronic
pancreatitis in Warsaw. Mater Med Pol 1990; 22:202-
4. [PMID 2132427]
13. Johnson CD, Hosking S. National statistics for
diet, alcohol consumption, and chronic pancreatitis in
England and Wales, 1960-88. Gut 1991; 32:1401-5.
[PMID 1752477]
14. Jaakkola M, Nordback I. Pancreatitis in Finland
between 1970 and 1989. Gut 1993; 34:1255-60. [PMID
15. Cavallini G, Frulloni L, Pederzoli P, Talamini G,
Bovo P, Bassi C, et al. Long-term follow-up of patients
with chronic pancreatitis in Italy. Scand J Gastroenterol
1998; 33:880-9. [PMID 9754738]
16. Díte P, Starý K, Novotný I, Precechtelová M,
Dolina J, Lata J, Zboril V. Incidence of chronic
pancreatitis in the Czech Republic. Eur J Gastroenterol
Hepatol 2001; 13:749-50. [PMID 11434607]
17. Dani R, Mott CB, Guarita DR, Nogueira CE.
Epidemiology and etiology of chronic pancreatitis in
Brazil: a tale of two cities. Pancreas 1990; 5:474-8.
[PMID 2381901]
18. Smith DI, Burvill PW. Relationship between male
pancreatitis morbidity and alcohol consumption in
Western Australia, 1971-84. Br J Addict 1990; 85:655-
8. [PMID 2354282]
19. Marks IN, Girdwood AH, Bank S, Louw JH. The
prognosis of alcohol-induced calcific pancreatitis. S
Afr Med J 1980 19; 57:640-3 [PMID 7376029]
20. Otsuki M. Chronic pancreatitis in Japan:
epidemiology, prognosis, diagnostic criteria, and future
problems. J Gastroenterol 2003; 38:315-26. [PMID
21. Mohan V, Premalatha G, Pitchumoni CS. Tropical
chronic pancreatitis: an update. J Clin Gastroenterol
2003; 36:337-46. [PMID 12642742]
22. Talukdar R, Saikia N, Singal DK, Tandon R.
Pancreatology 2006; 6:440-9. [PMID 16847381]
23. Morselli-Labate AM, Fantini L, Pezzilli R.
Hydrogen sulfide, nitric oxide and a molecular mass 66
u substance in the exhaled breath of chronic
pancreatitis patients. Pancreatology 2007; 7:497-504.
[PMID 17912017]
24. Kuroda J, Suda K, Hosokawa Y. Periacinar
collagenization in patients with chronic alcoholism.
Pathol Int 1998; 48:857-68. [PMID 9832054]
25. Martin E, Bedossa P. Diffuse fibrosis of the
pancreas: a peculiar pattern of pancreatitis in alcoholic
cirrhosis. Gastroenterol Clin Biol 1989; 13:579-84.
[PMID 2753305]

Page 5
JOP. J Pancreas (Online) 2008; 9(5):588-592.
JOP. Journal of the Pancreas - - Vol. 9, No. 5 - September 2008. [ISSN 1590-8577]
26. Suda K, Takase M, Takei K, Nakamura T, Akai J,
Nakamura T. Histopathologic study of coexistent
pathologic states in pancreatic fibrosis in patients with
chronic alcohol abuse: two distinct pathologic fibrosis
entities with different mechanisms. Pancreas 1996;
12:369-72. [PMID 8740404]
27. Rommens JM, Iannuzzi MC, Kerem B, Drumm
ML, Melmer G, Dean M, et al. Identification of the
cystic fibrosis gene: chromosome walking and
jumping. Science 1989; 245:1059-65. [PMID 2772657]
28. Whitcomb DC, Gorry MC, Preston RA, Furey W,
Sossenheimer MJ, Ulrich CD, et al. Hereditary
pancreatitis is caused by a mutation in the cationic
trypsinogen gene. Nat Genet 1996; 14:141-5. [PMID
29. Witt H, Luck W, Hennies HC, Classen M, Kage A,
Lass U, Landt O, Becker M. Mutations in the gene
encoding the serine protease inhibitor, Kazal type 1 are
associated with chronic pancreatitis. Nat Genet 2000;
25:213-6. [PMID 10835640]
30. Bhatia E, Choudhuri G, Sikora SS, Landt O, Kage
A, Becker M, Witt H. Tropical calcific pancreatitis:
strong association with SPINK1 trypsin inhibitor
mutations. Gastroenterology 2002; 123:1020-5. [PMID
31. Schneider A, Suman A, Rossi L, Barmada MM,
Beglinger C, Parvin S, et al. SPINK1/PSTI mutations
are associated with tropical pancreatitis and type II
diabetes mellitus in Bangladesh. Gastroenterology
2002; 123:1026-30. [PMID 12360464]
32. Bhatia E, Durie P, Zielenski J, Lam D, Sikora SS,
Choudhuri G, Tsui LC. Mutations in the cystic fibrosis
transmembrane regulator gene in patients with tropical
calcific pancreatitis. Am J Gastroenterol 2000;
95:3658-9. [PMID 11151920]
33. Pezzilli R, Morselli-Labate AM, Mantovani V,
Romboli E, Selva P, Migliori M, Corinaldesi R, Gullo
L. Mutations of the CFTR gene in pancreatic disease.
Pancreas 2003; 27:332-6. [PMID 14576497]
34. Sarles H, Sarles JC, Muratore R, Guien C. Chronic
inflammatory sclerosis of the pancreas--an autonomous
pancreatic disease? Am J Dig Dis 1961; 6:688-98.
[PMID 13746542]
35. Yoshida K, Toki F, Takeuchi T, Watanabe S,
Shiratori K, Hayashi N. Chronic pancreatitis caused by
an autoimmune abnormality. Proposal of the concept of
autoimmune pancreatitis. Dig Dis Sci 1995; 40:1561-8.
[PMID 7628283]
36. Pearson RK, Longnecker DS, Chari ST, Smyrk
TC, Okazaki K, Frulloni L, Cavallini G. Controversies
in clinical pancreatology: autoimmune pancreatitis:
does it exist? Pancreas 2003; 27:1-13. [PMID
37. Das SK, Balakrishnan V, Vasudevan DM.
Alcohol: its health and social impact in India. Natl Med
J India 2006; 19:94-9. [PMID 16756199]
38. WHO. WHO Global Status Report on Alcohol
2004. World Health Organization Department of
Mental Health and Substance Abuse Geneva 2004.
39. Gullo L, Barbara L, Labò G. Effect of cessation of
alcohol use on the course of pancreatic dysfunction in
alcoholic pancreatitis. Gastroenterology 1988;
95:1063-8. [PMID 3410221]
40. Ryu JK, Lee JK, Kim YT, Lee DK, Seo DW, Lee
KT, et al. Clinical features of chronic pancreatitis in
Korea: a multicenter nationwide study. Digestion 2005;
72:207-11. [PMID 16260866]
41. Garg PK, Tandon RK. Survey on chronic
pancreatitis in the Asia-Pacific region. J Gastroenterol
Hepatol 2004; 19:998-1004. [PMID 15304116]
42. Frulloni L, Gabbrielli A, Pezzilli R, Zerbi A,
Cavestro GM, Marotta F, et al. Chronic pancreatitis:
report from a multicenter Italian survey
(PancroInfAISP) on 893 patients. Digestive and Liver
Disease 2008 (in press).
43. Pezzilli R, Morselli-Labate AM, Fantini L,
Campana D, Corinaldesi R. Assessment of the quality
of life in chronic pancreatitis using Sf-12 and EORTC
Qlq-C30 questionnaires. Dig Liver Dis 2007; 39:1077-
86. [PMID 17692582]
44. Montalto G, Carroccio A, Soresi M, Ficano L,
Notarbartolo A. Chronic pancreatitis in Sicily.
Preliminary reports. Ital J Gastroenterol 1990; 22:33-5.
[PMID 2131926]
45. Balakrishnan V, Unnikrishnan AG, Thomas V,
Choudhuri G, Veeraraju P, Singh SP, et al. Chronic
pancreatitis. A prospective nationwide study of 1,086
Subjects from India. JOP. J Pancreas (Online) 2008:
9:593-600. [PMID 18762690

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