Dig Dis Sci (2010) 55:3610–3616
DOI 10.1007/s10620-010-1175-8
ORIGINAL ARTICLE
Recurrent Acute Pancreatitis: Clinical Profile and an Approach
to Diagnosis
K. G. Sajith • Ashok Chacko • Amit Kumar Dutta
Received: 2 November 2009 / Accepted: 19 February 2010 / Published online: 16 March 2010
Ó Springer Science+Business Media, LLC 2010
Abstract
Background and Aims Though recurrent acute pancrea-
titis is often seen in clinical practice, there are few com-
prehensive articles on this entity. The aim of this study
therefore was to assess the etiological and clinical profile as
well as diagnostic yield of non-invasive and invasive tests
in this group of patients.
Methods All patients with recurrent acute pancreatitis
seen from 2002 to 2007 were included in the study, ret-
rospectively. Clinical information, investigation, and
treatment data were collected for all patients by a stan-
dardized review of medical charts. Diagnostic tests were
grouped into level one (non-invasive) and level two
(invasive) tests and their yield was assessed. Comparison
was made between the group with known etiology and
idiopathic group to look for significant differences.
Results A total of 188 patients with recurrent acute pan-
creatitis were seen during the study period. Common eti-
ological factors were biliary disease (37%), pancreas
divisum (8.5%) and alcohol (6.4%). Multiple etiologies
were seen in 7% of cases, and no cause was found in
32.4%. The diagnostic yield of level-one investigation
(non-invasive) was 29.3%. Level-two tests (invasive)
identified presumptive etiologies in 38.3% of cases. Com-
plications developed in 12.2% and there was no mortality.
Clinical features and complications were similar in the
idiopathic group and those with known etiology.
Conclusions Etiological diagnosis was obtained in 67.6%
of patients after comprehensive diagnostic work up.
Diagnosis in the majority of patients could only be reached
K. G. Sajith
A. Chacko (&)
A. K. Dutta
Department of Gastrointestinal Sciences, Christian Medical
College, Vellore, Tamil Nadu 632 004, India
e-mail: gastro@cmcvellore.ac.in
123
after invasive tests (bile crystal analysis, EUS, ERCP).
Early diagnosis and etiology-based therapy is the key to
optimum patient outcome.
Keywords Recurrent acute pancreatitis
Etiology

Non-invasive and invasive investigation
Introduction
Acute pancreatitis is a common condition characterized by
inflammation of pancreatic tissue in the absence of mor-
phological changes on imaging studies [1]. About 2–10%
of patients succumb to the initial illness [2] and another
10–35% go on to have recurrent episodes of acute pan-
creatitis [3–5]. Considering the potential burden of recur-
rent acute pancreatitis (RAP), it is surprising that there are
few comprehensive articles on this entity [3–5]. Most
papers deal with an etiological and/or therapeutic subset of
RAP [6–10]. Studies on etiology show that a cause for RAP
can be determined in 70–90% of patients, the remaining
being grouped as idiopathic recurrent acute pancreatitis
(IRAP) [5–7, 11, 12]. A paucity of data on the etiological
profile of RAP in Asia and the recent introduction of new
technology necessitates fresh data to be generated to plan
efficient and cost-effective strategies for diagnosis and
management of this disease. Previous studies suggest that
RAP has a lower mortality than a single episode of pan-
creatitis [13, 14]. IRAP has been found to have a higher
morbidity and mortality than the group where an etiology is
detected [5, 13]. We do not know whether this is still true.
The purpose of this paper is: (1) to report our experience
with RAP and provide a more complete and updated pic-
ture of etiological and clinical profile of this disease and (2)
Dig Dis Sci (2010) 55:3610–3616
assess diagnostic yield of invasive and non-invasive tests
and generate a diagnostic algorithm.
Methodology
All patients seen in the Department of Gastrointestinal
Sciences, Christian Medical College and Hospital, Vellore,
India, from January 2002 to December 2007 were screened
retrospectively. Patients with a diagnosis of recurrent acute
pancreatitis were included in the study. Clinical informa-
tion and laboratory and treatment data were collected for
all patients by a standardized review of medical charts
using uniform structured data forms.
Recurrent acute pancreatitis (RAP) was defined as two
or more documented episodes of abdominal pain, typical of
acute pancreatitis, more than 2 months apart and at least
one of the following: (1) serum amylase or lipase elevation
more than three times the upper limit of normal, (2) fea-
tures of acute pancreatitis on imaging (ultrasound/CECT)
[15]. Patients with features suggestive of chronic pancre-
atitis including calcifications, ductal dilatation, and paren-
chymal atrophy were excluded [16]. An attack of
pancreatitis was considered to be severe if there was multi-
organ dysfunction or local complications, namely, fluid
collection, necrosis, or abscess [1].
Initial etiological evaluation of the patients (level 1)
consisted of liver function tests, fasting serum calcium and
lipid profile, CA19-9 and noninvasive imaging (ultrasound
and/or CECT abdomen). Patients who remained undiag-
nosed after level 1 investigations were subjected to level 2
evaluations. This consisted of duodenal bile examination
for microliths in patients with intact gall bladder and at
least one of the sophisticated/invasive imaging techniques
(MRCP, ERCP, EUS). The duodenal bile (5–10 ml) was
collected during endoscopy, centrifuged at 2,000 9 g for
10 min, and then the sediment examined under direct and
polarizing microscope. Microliths were diagnosed as a
cause of RAP if more than five cholesterol or calcium bi-
lirubinate crystals were present in a patient with intact gall
bladder [6]. Genetic tests for RAP were not performed.
Patients were labeled as having IRAP if the above inves-
tigations were normal. Biliary pancreatitis was considered
the cause of RAP if there was jaundice and/or abnormal
LFT with cholelithiasis, gall bladder sludge, choledocho-
lithiasis, or biliary microliths [4]. Hypertriglyceridemia
was considered the cause when serum triglyceride was
more than 500 mg/dl [17]. Hypercalcemia was considered
the cause when the fasting serum calcium was elevated
(normal range, 8.5–10.5 mg/dl) [18]. Pancreatitis was
attributed to alcohol use if the patient consumed an average
of 80 g of alcohol daily for more than 5 years or had an
alcoholic binge within a week prior to the acute attack [4].
3611
Anomalous union of pancreaticobiliary duct was diagnosed
when the junction of the bile duct and the pancreatic duct
was at a proximal site with a long ([15 mm) common
pancreaticobiliary channel [19].
The etiology and clinicoepidemiological profile of
patients were analyzed. The diagnostic yield of level-one
and level-two investigations were also assessed. A com-
parison was made between the group with known etiology
and the idiopathic group to look for significant differences.
Statistical Analysis
The descriptive data are presented as mean values with
standard deviations or median with range for continuous
variables and as number or proportions for categorical
variables. Comparison between the idiopathic group and
the rest of the patients was done by Fischer’s exact test for
categorical variables and Student’s t test or Mann–Whitney
U test for continuous variables. A two-tailed p value
of B0.05 was considered significant. All analysis was
performed in SPSS for Windows Version 11.
Results
During the 6-year study period, 188 patients with RAP
were identified. Demographic and clinical profile of the
patients is shown in Table 1. The mean age of the patients
was 33 years and 132 (70.2%) were males. The majority of
the patients (75%) were from eastern India. The median
number of episodes of acute pancreatitis was 3 (range
2–10) and the median number of hospital admissions was 2
(range 1–6). Twenty-seven patients (14.4%) had severe
pancreatitis. Complications were detected in 23 (12.2%)
patients. There was no mortality.
A definite etiology was established in 55 (29.3%)
patients after applying level-one investigations (Fig. 1). All
patients had an intact gall bladder at presentation. Biliary
disease was the cause of RAP in 24 patients and alcohol in
12 patients. Metabolic causes were present in eight patients
(dyslipidemia six, hypercalcemia two), blunt abdominal
trauma sustained during road traffic accidents in two,
ascariasis in two and carcinoma pancreas in one patient.
Six patients had more than one etiology. A history of intake
of drugs causing pancreatitis or family history of pancre-
atitis was not elicited from any of our patients.
An etiological diagnosis was obtained in 72 of the
remaining 133 patients after application of level-two
investigations (Fig. 1). Biliary microlithiasis, the com-
monest etiology was detected in 46 patients followed by
structural pancreaticobiliary anomalies in 19 patients
(pancreas divisum in 16, anomalous pancreaticobiliary duct
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3612 Dig Dis Sci (2010) 55:3610–3616

Table 1 Demographic and

Age (mean ± SD) (years) 32.6 ± 14
clinical profile of patients
(n = 188) Sex (male) 132 (70.2%)
Region (east/south) 141/47(75%/25%)
Number of episodes of AP (median, range) 3 (2–10)
Number of hospital admissions for AP (median, range) 2 (1–6)
Pancreatic pseudocyst 15 (8%)
Pancreatic necrosis 3 (1.6%)
Pancreatic abscess 3 (1.6%)
Pleural effusion 14 (7.4%)
Respiratory failure 1 (0.5%)
Renal failure 5 (2.7%)
Splanchnic venous thrombosis 4 (2.2%)
Splenic artery pseudoaneurysm 1 (0.5%)
Overall complications 23 (12.2%)
Severe pancreatitis 27 (14.36%)
Mortality 0

Fig. 1 Etiological profile of

Patients with recurrent acute
patients with recurrent acute
pancreatitis
pancreatitis. US/CT,
ultrasonogram/computed 1.Gall stone/CBD stone 24
N=188 Level 1 investigations 2.Alcohol 12
tomography; BM, biliary
microliths; PD, pancreas 3.Hypercalcemia 2
divisum; APBU, anomalous 4.Hypertriglyceridemia 6
Liver function tests 5.Carcinoma pancreas 1
pancreatobiliary union; DD, N=55
Lipid profile 6.Trauma 2
duodenal diverticulum; ERCP,
Serum calcium 7.Ascariasis 2
endoscopic retrograde CA 19-9
cholangiopancreatography; 8.Gall stone and 2
US/CT Abdomen hypertriglyceridemia
MRCP, magnetic resonance
cholangiopancreatography; 9.Alcohol and gall stone 3
EUS, endoscopic 10.Alcohol and trauma 1
ultrasonography N=133 Level 2 investigations
1.BM 46
ERCP/MRCP/EUS 2.PD 16
N=72
Bile for Microliths 3.APBU 1
4.Choledochal cyst 1
5.DD 1
6.BM+PD 4
N=61 7.BM+ABPU 2
8.BM+DD 1

Idiopathic = 61

union in one, choledochal cyst in one, and duodenal
diverticulum in one). Seven patients had multiple etiolog-
ical factors. Overall, 13 patients (after level-one and level-
two investigations) had multiple etiologies. Clinical pro-
file of patients with multiple etiologies (mean age:
32.2 ± 14.5 years; male: 84.6%; east India: 61.5%) and
complications were similar to patients with a single
etiology.
After complete work-up (level-one and two evaluation),
an etiology was detected in 127 patients (67.6%). No eti-
ology was detected in 61 (32.4%) patients and they were
labeled as having idiopathic recurrent acute pancreatitis
(IRAP). The clinical and demographic profile of the IRAP
group was similar to the patients where an etiology was
detected (Table 2).
The treatment of patients with RAP was tailored
according to the etiology. Patients with a stone in the bile
duct (n = 6) underwent stone extraction preoperatively by
ERCP, and if unsuccessful (n = 1), were advised intraop-
erative stone clearance. Cholecystectomy was performed
for patients with cholelithiasis. Strict abstinence from
alcohol was advised in the group with alcohol-related RAP.

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Dig Dis Sci (2010) 55:3610–3616 3613

Table 2 Comparison of clinical

Idiopathic (n = 61) Others (n = 127) p value
and demographic profiles of the
idiopathic group with the rest of Age (years) 32.5 ? 15.6 32.7 ? 12.9 0.93
the patients
Sex (male) 44 (72.1%) 88 (69.35%) 0.74
Region (E/S) 47/14 (77%/23%) 94/33 (74%/26%) 0.72
Number of episodes of AP 3 (2–10) 3 (2–10) 0.87
(median, range)
Number of hospital admissions 2 (1–6) 2 (1–6) 0.94
for AP (median, range)
Pancreatic pseudocyst 5 (8.2%) 10 (7.9%) 1.0
Pancreatic necrosis 2 (3.3%) 1 (0.8%) 0.25
Pancreatic abscess 0% 3 (2.4%) 0.56
Pleural effusion 5 (8.2%) 9 (7.1%) 0.77
Renal failure 1 (1.6%) 4 (3.1%) 1.0
Overall complications 7 (11.5%) 16 (12.6%) 1.0
Severe pancreatitis 10 (16.4%) 17 (13.4%) 0.7

Lipid-lowering therapy was started in all patients with
dyslipidemia. Deworming with albendazole was done for
patients with ascariasis. Forty-one patients with biliary
microlithiasis were started on ursodeoxycholic acid
(UDCA). Twenty-nine (70.7%) of these patients were
asymptomatic during a follow-up period ranging from
6 months to 1 year at which time either a biliary sphinc-
terotomy (n = 25) or cholecystectomy (n = 4) was per-
formed. Among the 25 patients who had biliary
sphincterotomy, 23 (92%) were asymptomatic at a median
follow-up of 2 years. Three of the patients who had cho-
lecystectomy were followed for a median of 3 years during
which period two were symptom free. Of the remaining 12
patients started on UDCA, three developed chronic pan-
creatitis, two continued to have RAP, one underwent lap
cholecystectomy at another hospital and six were lost to
follow-up. Eleven patients with pancreas divisum under-
went accessory papilla sphincterotomy, of whom eight
(73%) were symptom free at a median follow-up of
2.5 years. The remaining five patients with biliary micro-
lithiasis and five patients with PD were not followed-up
after the acute episode for etiology-directed therapy. A
follow-up of all the patients is currently ongoing, and a
definite comment on outcome can be made only after long-
term follow-up.
Discussion
During the past 6 years we have managed 188 patients with
RAP at our center. Though a frequently encountered entity
in clinical practice, few studies have focused on recurrent
acute pancreatitis [3–5]. Gullo et al. [3–5] described RAP
in patients from five European countries while Gao et al.
and Zhang et al. [3–5] described this entity from China.
Comparison of age shows that most of our patients were
younger adults (third and fourth decade) when compared to
other reports where patients presented 10–20 years later.
Prevalence of RAP was higher in males in our study as in
other studies [3, 5]. The majority of our patients were seen
during the third episode of acute pancreatitis. In contrast,
most patients in the European and Chinese studies were
seen during the second episode [3, 5]. This may be due to
either delayed health care seeking behavior of Indian
patients or a delay in referral by primary-care physicians.
Delayed presentation in the current study suggests the need
to educate the patients and medical fraternity about the
nature and morbidity of RAP.
The etiology of recurrent acute pancreatitis has been
classified as: (1) toxic-metabolic: alcohol, hypertriglyceri-
demia, hypercalcemia, drugs; (2) mechanical-obstructive:
biliary stones/microlithiasis, structural abnormalities (con-
genital or acquired), trauma; and (3) miscellaneous [20]. In
the current study, 94 (50%) patients had mechanical-
obstructive pancreatitis, 20 (10.6%) had toxic-metabolic
pancreatitis, 13 (7%) had multiple etiologies and 61 (32.4%)
had idiopathic pancreatitis. Similar to most of the earlier
studies, biliary pancreatitis (due to cholelithiasis, choledo-
cholithiasis, and microlithiasis) was the most common eti-
ology of RAP (37%) in our study [3, 4, 12, 21–24]. As in
other studies, biliary microliths was the predominant cause
of biliary pancreatitis [23, 24]. Microlithiasis as a cause of
RAP has been debated [25]. Reduction of the risk of RAP
after cholecystectomy and UDCA however suggest that
microliths can cause RAP [26]. Pancreas divisum (8.5%)
was the next most common cause of RAP in the current
study. Pancreas divisum (PD) as a cause of acute pancreatitis
is controversial, as some studies show that the prevalence of

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3614
PD in acute pancreatitis is similar to the general population
[27]. However, the high prevalence of PD in patients with
acute pancreatitis in other studies and the favorable response
after accessory papilla sphincterotomy favor PD as a cause
of RAP [28–34]. Alcohol was the etiology in a small pro-
portion of our patients (6.4%). This is in contrast to a recent
multicenter European study where alcohol was the most
common etiology in 57% of the patients [5]. A reason for the
reduced frequency of biliary pancreatitis in recent Western
studies may be the tendency to perform early cholecystec-
tomy or biliary sphincterotomy after an episode of acute
pancreatitis. Other structural causes like anomalous pan-
creato-biliary union, choledochal cyst, duodenal diverticu-
lum, and metabolic causes like hypertriglyceridemia and
hypercalcemia were seen in a small number of patients [4, 8,
19, 20]. Multiple etiologies were detected in 13 (7%)
patients. As there are no criteria to determine the dominant
etiology responsible for RAP, it was difficult to plan therapy
for these patients.
An important observation from our study is that after
noninvasive investigations (level one), available at most
centers, an etiology for RAP was identified in only 30% of
patients (Fig 1). Invasive investigations (ERCP, EUS, bile
crystal analysis in patients with intact gall bladder) and/or
MRCP (level-two investigations), usually available at
tertiary care centers, were needed to establish presumptive
etiology in an additional 38% of patients. This suggests
that the algorithm to evaluate etiology for RAP should
initially be noninvasive tests, which must then be followed
by invasive tests if no etiology is detected. The above also
suggests that prompt referral to a center where level-two
investigations are available is the key to establishing an
early etiological diagnosis and planning effective treat-
ment. This will prevent recurrent attacks of pancreatitis
and reduce morbidity, mortality, and progression to
chronic pancreatitis [5, 35]. Many studies have reported
the diagnostic utility of ERCP, bile crystal analysis,
endoscopic ultrasound (EUS), and MRCP in patients with
RAP [6, 7, 36, 37]. Feller et al. [37] obtained a diagnosis
in 32% of patients labeled ‘idiopathic’ RAP after ERCP.
Coyle and colleagues investigated 90 patients with ‘idio-
pathic’ acute or recurrent acute pancreatitis using ERCP
with sphincter of Oddi manometry (SOM), bile analysis,
and EUS, and achieved a diagnosis in about 70% patients
[36]. In an American study of 126 patients with ‘idio-
pathic’ recurrent acute pancreatitis, etiology was identified
in 79% after ERCP, bile crystal analysis, and SOM [6]. As
ERCP is associated with serious complications, including
pancreatitis, bleeding, and perforation, its use as a purely
diagnostic modality is on the decline [38]. EUS with its
potential to detect small CBD stones, biliary sludge,
congenital structural anomalies, and early chronic
pancreatitis, is emerging as an important less-invasive
123
Dig Dis Sci (2010) 55:3610–3616
alternative to ERCP [39, 40]. MRCP, a non-invasive
modality has been shown to be effective in the diagnosis
of CBD stones and congenital structural abnormalities
[41].
Sixty-one patients (32%) were labeled as having idio-
pathic recurrent acute pancreatitis (IRAP) as no etiology
was detected after level-one and level-two investigations
(Fig. 1). The percentage of patients with IRAP in our
study is similar to studies from China, but higher than a
European study where 10.4% of patients had IRAP [3, 5].
Studies on patients with IRAP have shown that SOD is
responsible for RAP in 15–30% of patients [11, 20, 42].
Genetic studies suggest that CFTR and cationic trypsino-
gen mutations are associated with RAP [43, 44]. Thomas
et al. [45] have shown that 33% of patients labeled as
IRAP on long-term follow up developed chronic pancre-
atitis. What could the etiology be in our patients with
IRAP? It may be due to SOD or genetic factors not
evaluated in this study, or early chronic pancreatitis not
detected by imaging studies.
Twenty-seven patients (14.4%) in our study had severe
pancreatitis. Complications were detected in 23 (12.2%)
patients. Pancreatic pseudocyst (8%) was the most common
complication followed by pleural effusion (7%), renal fail-
ure (3%), and splanchnic venous thrombosis (2%). There
was no mortality. These data are similar to the study by
Zhang et al. [4] where 17% of patients with RAP had severe
pancreatitis. Similar to previous studies, our study also
suggests that RAP has a lower mortality that a single episode
of pancreatitis [3, 14]. Table 2 compares the clinical profile
of patients with IRAP and other etiologies and shows that the
rate of severe pancreatitis and complications is similar in
both groups. This is in contrast to data from other studies that
show IRAP to be a more severe disease [5]. A possible
explanation for this is that these studies had a large number
of patients with alcoholic RAP where severity of disease and
mortality are lower than biliary or idiopathic RAP [5]. The
potential limitation of our study is its retrospective nature.
However, a standardized approach to evaluate and treat
patients with pancreatitis followed at our center minimizes
the chance of missing data.
In conclusion, this study demonstrates that biliary stone
disease, pancreas divisum, and alcoholism are common
causes of RAP. Diagnosis could only be reached in the
majority of patients after use of invasive tests (ERCP, EUS,
and bile crystal analysis) available at tertiary care centers.
Early diagnosis and etiology-based therapy are the keys to
prevent recurrent attacks and to obtain an optimum patient
outcome.
Acknowledgments Conflict of Interest Statement The authors
declare that there are no conflicts of interests. No grants were received
for this study.
Dig Dis Sci (2010) 55:3610–3616
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