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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 after invasive tests (bile crystal analysis, EUS, ERCP).


Background and Aims Though recurrent acute pancrea- Early diagnosis and etiology-based therapy is the key to
titis is often seen in clinical practice, there are few com- optimum patient outcome.
prehensive articles on this entity. The aim of this study
therefore was to assess the etiological and clinical profile as Keywords Recurrent acute pancreatitis  Etiology 
well as diagnostic yield of non-invasive and invasive tests Non-invasive and invasive investigation
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 Introduction
treatment data were collected for all patients by a stan-
dardized review of medical charts. Diagnostic tests were Acute pancreatitis is a common condition characterized by
grouped into level one (non-invasive) and level two inflammation of pancreatic tissue in the absence of mor-
(invasive) tests and their yield was assessed. Comparison phological changes on imaging studies [1]. About 2–10%
was made between the group with known etiology and of patients succumb to the initial illness [2] and another
idiopathic group to look for significant differences. 10–35% go on to have recurrent episodes of acute pan-
Results A total of 188 patients with recurrent acute pan- creatitis [3–5]. Considering the potential burden of recur-
creatitis were seen during the study period. Common eti- rent acute pancreatitis (RAP), it is surprising that there are
ological factors were biliary disease (37%), pancreas few comprehensive articles on this entity [3–5]. Most
divisum (8.5%) and alcohol (6.4%). Multiple etiologies papers deal with an etiological and/or therapeutic subset of
were seen in 7% of cases, and no cause was found in RAP [6–10]. Studies on etiology show that a cause for RAP
32.4%. The diagnostic yield of level-one investigation can be determined in 70–90% of patients, the remaining
(non-invasive) was 29.3%. Level-two tests (invasive) being grouped as idiopathic recurrent acute pancreatitis
identified presumptive etiologies in 38.3% of cases. Com- (IRAP) [5–7, 11, 12]. A paucity of data on the etiological
plications developed in 12.2% and there was no mortality. profile of RAP in Asia and the recent introduction of new
Clinical features and complications were similar in the technology necessitates fresh data to be generated to plan
idiopathic group and those with known etiology. efficient and cost-effective strategies for diagnosis and
Conclusions Etiological diagnosis was obtained in 67.6% management of this disease. Previous studies suggest that
of patients after comprehensive diagnostic work up. RAP has a lower mortality than a single episode of pan-
Diagnosis in the majority of patients could only be reached 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.
K. G. Sajith  A. Chacko (&)  A. K. Dutta
The purpose of this paper is: (1) to report our experience
Department of Gastrointestinal Sciences, Christian Medical
College, Vellore, Tamil Nadu 632 004, India with RAP and provide a more complete and updated pic-
e-mail: gastro@cmcvellore.ac.in ture of etiological and clinical profile of this disease and (2)

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assess diagnostic yield of invasive and non-invasive tests Anomalous union of pancreaticobiliary duct was diagnosed
and generate a diagnostic algorithm. 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].
Methodology The etiology and clinicoepidemiological profile of
patients were analyzed. The diagnostic yield of level-one
All patients seen in the Department of Gastrointestinal and level-two investigations were also assessed. A com-
Sciences, Christian Medical College and Hospital, Vellore, parison was made between the group with known etiology
India, from January 2002 to December 2007 were screened and the idiopathic group to look for significant differences.
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 Statistical Analysis
all patients by a standardized review of medical charts
using uniform structured data forms. The descriptive data are presented as mean values with
Recurrent acute pancreatitis (RAP) was defined as two standard deviations or median with range for continuous
or more documented episodes of abdominal pain, typical of variables and as number or proportions for categorical
acute pancreatitis, more than 2 months apart and at least variables. Comparison between the idiopathic group and
one of the following: (1) serum amylase or lipase elevation the rest of the patients was done by Fischer’s exact test for
more than three times the upper limit of normal, (2) fea- categorical variables and Student’s t test or Mann–Whitney
tures of acute pancreatitis on imaging (ultrasound/CECT) U test for continuous variables. A two-tailed p value
[15]. Patients with features suggestive of chronic pancre- of B0.05 was considered significant. All analysis was
atitis including calcifications, ductal dilatation, and paren- performed in SPSS for Windows Version 11.
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 Results
collection, necrosis, or abscess [1].
Initial etiological evaluation of the patients (level 1) During the 6-year study period, 188 patients with RAP
consisted of liver function tests, fasting serum calcium and were identified. Demographic and clinical profile of the
lipid profile, CA19-9 and noninvasive imaging (ultrasound patients is shown in Table 1. The mean age of the patients
and/or CECT abdomen). Patients who remained undiag- was 33 years and 132 (70.2%) were males. The majority of
nosed after level 1 investigations were subjected to level 2 the patients (75%) were from eastern India. The median
evaluations. This consisted of duodenal bile examination number of episodes of acute pancreatitis was 3 (range
for microliths in patients with intact gall bladder and at 2–10) and the median number of hospital admissions was 2
least one of the sophisticated/invasive imaging techniques (range 1–6). Twenty-seven patients (14.4%) had severe
(MRCP, ERCP, EUS). The duodenal bile (5–10 ml) was pancreatitis. Complications were detected in 23 (12.2%)
collected during endoscopy, centrifuged at 2,000 9 g for patients. There was no mortality.
10 min, and then the sediment examined under direct and A definite etiology was established in 55 (29.3%)
polarizing microscope. Microliths were diagnosed as a patients after applying level-one investigations (Fig. 1). All
cause of RAP if more than five cholesterol or calcium bi- patients had an intact gall bladder at presentation. Biliary
lirubinate crystals were present in a patient with intact gall disease was the cause of RAP in 24 patients and alcohol in
bladder [6]. Genetic tests for RAP were not performed. 12 patients. Metabolic causes were present in eight patients
Patients were labeled as having IRAP if the above inves- (dyslipidemia six, hypercalcemia two), blunt abdominal
tigations were normal. Biliary pancreatitis was considered trauma sustained during road traffic accidents in two,
the cause of RAP if there was jaundice and/or abnormal ascariasis in two and carcinoma pancreas in one patient.
LFT with cholelithiasis, gall bladder sludge, choledocho- Six patients had more than one etiology. A history of intake
lithiasis, or biliary microliths [4]. Hypertriglyceridemia of drugs causing pancreatitis or family history of pancre-
was considered the cause when serum triglyceride was atitis was not elicited from any of our patients.
more than 500 mg/dl [17]. Hypercalcemia was considered An etiological diagnosis was obtained in 72 of the
the cause when the fasting serum calcium was elevated remaining 133 patients after application of level-two
(normal range, 8.5–10.5 mg/dl) [18]. Pancreatitis was investigations (Fig. 1). Biliary microlithiasis, the com-
attributed to alcohol use if the patient consumed an average monest etiology was detected in 46 patients followed by
of 80 g of alcohol daily for more than 5 years or had an structural pancreaticobiliary anomalies in 19 patients
alcoholic binge within a week prior to the acute attack [4]. (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 labeled as having idiopathic recurrent acute pancreatitis
diverticulum in one). Seven patients had multiple etiolog- (IRAP). The clinical and demographic profile of the IRAP
ical factors. Overall, 13 patients (after level-one and level- group was similar to the patients where an etiology was
two investigations) had multiple etiologies. Clinical pro- detected (Table 2).
file of patients with multiple etiologies (mean age: The treatment of patients with RAP was tailored
32.2 ± 14.5 years; male: 84.6%; east India: 61.5%) and according to the etiology. Patients with a stone in the bile
complications were similar to patients with a single duct (n = 6) underwent stone extraction preoperatively by
etiology. ERCP, and if unsuccessful (n = 1), were advised intraop-
After complete work-up (level-one and two evaluation), erative stone clearance. Cholecystectomy was performed
an etiology was detected in 127 patients (67.6%). No eti- for patients with cholelithiasis. Strict abstinence from
ology was detected in 61 (32.4%) patients and they were alcohol was advised in the group with alcohol-related RAP.

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

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

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