GASTROENTEROLOGY 2005;128:756 –763
CLINICAL MANAGEMENT
Loren Laine, M.D.
Clinical Management Editor
University of Southern California
Los Angeles, California
“Idiopathic” Pancreatitis
PETER DRAGANOV and CHRIS E. FORSMARK
Division of Gastroenterology, Hepatology, and Nutrition, University of Florida College of Medicine, Gainesville, Florida USA
Clinical Case
A 38-year-old previously healthy man is seen in the
emergency room with constant epigastric pain radi-
ating to the back, associated with nausea and vom-
iting. Pancreatitis is suspected due to marked ele-
vations in lipase and amylase. The patient takes no
medications and has no family history of pancreati-
tis. He has no history of trauma. His calcium, tri-
glyceride, and liver chemistries are normal. Right
upper quadrant ultrasound is normal. An abdomi-
nal CT scan shows mild enlargement of the pancreas
with stranding into the peripancreatic fat. The pa-
tient is admitted with a diagnosis of acute “idio-
pathic” pancreatitis.
Background
There are an extensive number of potential etiol-
ogies for acute pancreatitis (AP) (Table 1). Determining
the etiology of AP is of crucial importance for several
reasons. First, if the underlying cause of pancreatitis is
not treated the patient’s condition may deteriorate (eg,
ongoing bile duct obstruction during attack of biliary
pancreatitis). Second, recurrent attacks of pancreatitis
may occur if the underlying condition is not corrected
and in some cases they will be severe or might lead to the
development of chronic pancreatitis.1 Third, a serious
underlying disease requiring specific therapy (eg, pancre-
atic cancer) may be the precipitating factor for AP.
The cause for AP is easily identified in 70% to 90% of
patients after an initial evaluation consisting of history,
physical examination, focused laboratory testing, and
routine radiologic evaluation (Table 2).
The search for the etiology of an attack of AP begins
with a careful history and physical examination. A his-
tory of alcohol abuse, medication use, gallstone disease,
vasculitis, abdominal trauma, elevated triglycerides, re-
cent endoscopic retrograde cholangiopancreatography
(ERCP), prior abdominal surgery, inflammatory bowel
disease, or family history of pancreatitis can give clues as
to the origin of AP. Physical examination may also rarely
provide a clue as to the etiology of AP. The presence of
jaundice suggests gallstones, pancreatic or ampullary
neoplasm, choledochal cyst, or sphincter of Oddi dys-
function (SOD). Eruptive xanthomas on the extensor
surfaces of the extremities and the buttocks or tuberous
xanthomas found over the large joints of the hand sug-
gest hypertriglyceridemia as the cause.
The serum amylase and lipase levels are used to help
establish the diagnosis of AP but also may provide some
insight into the underlying etiology. Pancreatitis result-
ing from gallstones, microlithiasis, or drugs is typically
associated with the highest levels of amylase and lipase
and the degree of elevation of amylase tends to be greater
than lipase.2,3 Amylase and lipase levels are usually some-
what lower and equally abnormal when alcohol, hyper-
triglyceridemia, cancer, or chronic pancreatitis is the
underlying cause.2,3 Elevations of liver chemistries are
seen most commonly in patients with AP due to gall-
stones, pancreatic or ampullary neoplasm, microlithiasis,
choledochal cyst, choledochocele, and SOD. A number of
studies have attempted to analyze the predictive ability
of liver chemistries to identify patients with gallstone
pancreatitis. An elevation of the ALT of greater than or
equal to 150 IU/L (approximately a 3-fold elevation) is
associated with a 95% probability of gallstone pancre-
atitis.4 Similarly, a bilirubin level greater than 2.0
mg/dL is associated with gallstone pancreatitis.5 Al-
though elevated serum calcium or triglycerides may be
the cause of AP, during hospitalization these levels may
decrease to normal due to fasting (triglycerides) or ad-
ministration of intravenous fluids (calcium). Therefore,
© 2005 by the American Gastroenterological Association
0016-5085/05/$30.00
doi:10.1053/j.gastro.2005.01.037
March 2005 IDIOPATHIC PANCREATITIS 757

Table 1. Etiologies of Acute Pancreatitis

Alcohol Idiopathic
Autoimmune pancreatitis Infection
Biliary calculous disease Bacterial
Macrolithiasis (bile duct stone) Campylobacter jejuni
Microlithiasis (biliary crystals) Legionella
Biliary cystic disease Leptospirosis
Choledochal cyst Mycobacterium avium complex
Choledochocele/duplication cyst Mycobacterium tuberculosis
Congenital anomaly Mycoplasma
Annular pancreas Parasites/worms
Anomalous pancreato-biliary junction Ascaris lumbricoides
Pancreas divisum Clonorchis sinensis
Chronic pancreatitis Cryptosporidium
Duodenal obstruction Microsporidia
Afferent limb obstructed (Billroth II) Viral
Atresia Coxsackievirus
Crohn’s disease Cytomegalovirus
Diverticulum Echo virus
Drugs Epstein-Barr virus
Acetaminophen Hepatitis (A, B, C) virus
Azathioprine HIV
Didanosine Mumps virus
Erythromycin Rubella virus
Estrogen Varicella virus
Furosemide Metabolic
Histamine-2 receptor antagonists Hypercalcemia
Mercaptopurine Hyperlipidemia
Methyldopa Benign
Metronidazole Malignant
Nitrofurantoin Renal disease
Nonsteroidal anti-inflammatory agents Chronic renal failure
Pentamidine Dialysis related
Tetracycline Sphincter of Oddi dysfunction
Valproic acid Toxin
Genetic Organophosphate insecticides
Alfa 1-antitrypsin deficiency Scorpion bite
Cystic fibrosis Trauma
Hereditary pancreatitis Tropical
Iatrogenic Vasculitis
ERCP Polyarteritis nodosa
Abdominal surgery Systemic lupus erythematosus

levels should be measured at the time of admission, or if
that is not possible, after resolution of the pancreatitis.
Transabdominal ultrasound (US) and computed to-
mography (CT) are the two imaging modalities most
frequently used in patients with AP. These techniques
tend to be complementary. US is very good at detecting
gallbladder stones (accuracy of ⬎ 90%). The sensitivity
of US for the detection of dilated bile ducts ranges in
various studies from 55% to 91%.6 –9 The reported sen-
sitivity of US for the detection of common bile duct
(CBD) stones is limited and ranges from 20% to 75%.
Visualization of the pancreas with US in the face of
ongoing AP tends to be poor due to overlying intestinal
gas.10 From that perspective, US is most useful when
biliary pancreatitis is suspected, and in a similar vein to
evaluate for gallstones in patients with no obvious cause
for AP.
Contrast enhanced CT more accurately delineates the
pancreas but less accurately identifies gallstones. Abdom-
inal CT is of particular use to confirm the diagnosis of AP
if it is in question, to stage the severity of AP (by
detecting the presence of local complications such as
acute fluid collections, pancreatic abscess, pseudocyst,
and pancreatic necrosis) and when the etiology of the
pancreatic attack is unclear. It is important to obtain an
intravenous contrast-enhanced CT. A noncontrast CT
will be of very limited value since it will not detect
pancreatic necrosis and pancreatic neoplasm can easily be
missed.
There has been a concern that the use of intravenous
contrast media early in the course of AP might increase
or precipitate pancreatic necrosis. Decreased pancreatic
capillary flow rates after intravenous contrast administra-
tion have been observed in two animal studies.11,12 One
758 DRAGANOV AND FORSMARK
Table 2. Initial Evaluation of Acute Pancreatitis
Parameter
History and Physical examination
Alcohol abuse
Drug intake
Family history
Jaundice
Eruptive or tuberous xanthomas
Laboratory evaluation
Amylase and lipase elevated
⬎ 5 ⫻ upper limit of normal
Amylase and lipase elevated
⬎5 ⫻ upper limit of normal
Calcium
Liver function tests
Triglycerides
Radiological evaluation
Ultrasound (transabdominal)
CT
retrospective study found that patients who underwent
contrast-enhanced CT had longer hospitalization than
those who did not.13 In a cohort analytic study an
increased incidence of local and systemic complications
was observed in patients with mild AP who underwent
GASTROENTEROLOGY Vol. 128, No. 3
contrast enhanced CT.14 Since prospective and random-
Potential Etiology/Diagnosis ized human studies are not available, it is reasonable to
reserve contrast-enhanced CT scans for patients with
Alcohol severe AP, patients with smoldering AP that is slow to
Drugs improve, patients with suspected local complications,
Hereditary
Macrolithiasis (bile duct
and patients with an unclear etiology of the attack of AP.
stone) The use of magnetic resonance imaging (MRI) as an
Microlithiasis (biliary alternative imaging modality to CT has not been exten-
crystals)
sively studied but recently a gadolinium-enhanced dy-
Neoplasm (ampulla,
pancreas) namic MRI was found to be comparable to intravenous
Sphincter of Oddi contrast enhanced CT for the assessment of the severity of
dysfunction AP.15 Furthermore, magnetic resonance cholangiopan-
Hypertriglyceridemia
creatography (MRCP) done at the same time might have
Drugs the ability to identify choledocholithiasis more accu-
Macrolithiasis (bile duct rately than CT.15 In most centers, however, a transab-
stone)
Microlithiasis (biliary
dominal ultrasound and abdominal CT scan are the
crystals) primary radiologic tests.
Alcohol Patients in whom this initial evaluation does not
Chronic pancreatitis
reveal an underlying etiology are classified as having
Hyperlipemia
Neoplasm “idiopathic” acute pancreatitis (IAP). It is in these pa-
Hypercalcemia tients where one can consider a more extensive evalua-
Choledochocele tion. In most analyses, the most common explanations
Macrolithiasis (bile duct
stone) which are identified with a more extensive evaluation
Microlithiasis (biliary include microlithiasis, SOD dysfunction, pancreas divi-
crystals) sum, and other congenital abnormalities, pancreatic and
Neoplasm (ampulla,
pancreas)
ampullary neoplasm, and genetic causes.16 –21
Pancreatic head
inflammation
Pancreatic head pseudocyst Potential Management Strategies
Sphincter of Oddi
dysfunction
Based on the current evidence and a variety of
Hypertriglyceridemia expert opinions, the following 3 management strategies
can be considered in our patient with IAP: (1) expectant
Chronic pancreatitis approach with no further testing, (2) empiric cholecys-
Choledochal cyst
Choledochocele tectomy, and (3) further specialized diagnostic evalua-
Macrolithiasis (bile duct tion.
stone)
Microlithiasis (biliary No Further Testing
crystals)
Neoplasm (ampulla, The strategy of no further testing in patients
pancreas)
younger than 40 years of age is supported by two lines of
Annular pancreas
Choledochal cyst evidence. The medium term recurrence rate after an
Choledochocele initial attack of IAP is believed to be low.22 In a study
Chronic pancreatitis from the United Kingdom, 31 patients with a single
Macrolithiasis (bile duct
stone) episode of IAP were evaluated. All patients underwent an
Neoplasm (ampulla, evaluation consisting of history, physical examination,
pancreas) routine laboratory tests, and US, CT, or both. About
two-thirds of these patients also underwent ERCP, al-
though none had bile analysis, SOD manometry, or
sphincterotomy. During a median follow-up of 36
months only one patient had recurrent pancreatitis, lead-
ing to a recommendation that extensive evaluation of
unexplained AP be delayed until the second attack. The
second line of evidence favoring a conservative approach
March 2005
is that the incidence of malignant neoplasm as the un-
derlying cause of AP is low in patients ⬍ 40 years of age.
In a study presented only in abstract form, Choudari et al
found that only 3% patients with AP younger that 40
years had a pancreatic neoplasm. In contrast 21% of
patients aged 40 to 60, and 25% of patients aged older
than 60 years had a neoplastic process as the cause of
their AP.23 Based on these limited data the current
consensus is that no further testing is an acceptable
management strategy in young patients (⬍ 40 years)
with one mild episode of unexplained AP. If the patient
is older than 40 years of age, has experienced more than
one attack of AP, or the initial attack of AP was severe,
further investigation or therapy is indicated.
Empiric Cholecystectomy
The use of empiric cholecystectomy is supported
by both the high prevalence of occult microlithiasis (bile
crystals) in patients with IAP and by the high false-
negative rate of bile crystal analysis.21,24,25 Two prospec-
tive studies found a high prevalence of microlithiasis
(65% to 85%) in patients with IAP,26,21 and those who
underwent therapy with cholecystectomy had no further
attacks. A number of retrospective series, most available
only in abstract form, have found occult gallstones or
microlithiasis to be present in 37%– 89% of patients
with recurrent IAP.16 –20 Despite these findings the prev-
alence of microlithiasis as a cause of IAP remains con-
troversial. All published studies were conducted in ter-
tiary referral centers, and the majority are retrospective
case series with substantial selection bias. At present the
expert consensus is that empiric cholecystectomy is a
reasonable management approach in patients with IAP,
particularly those with recurrent attacks of pancreati-
tis.27,28
Further Specialized Investigation
A number of specialized test are available to fur-
ther attempt to define the etiology of an attack of AP
(Table 3).
Laboratory Evaluation. A number of studies have
identified mutations in patients with idiopathic pancre-
atitis, including mutations in the genes encoding cat-
ionic trypsinogen (PRSS1), pancreatic secretory trypsin
inhibitor (Serine Protease Inhibitor Kazal Type 1 or
SPINK-1), cystic fibrosis transmembrane conductance
regulator (CFTR), and ␣1-antitrypsin.29 –31 Mutations in
CFTR and SPINK-1, and to lesser extent PRSS1, have
been most strongly implicated as underlying etiological
factors in IAP.29 –31 The connection between ␣1-antitryp-
sin deficiency and IAP is questionable. A few case reports
and one systematic study suggest that deficiency in this
IDIOPATHIC PANCREATITIS 759
Table 3. Conditions That Can Cause Acute Pancreatitis and
Specialized Test That Can Detect Them
Condition Diagnostic modalities
Autoimmune pancreatitis Antinuclear antibody, Ig G4,
ERCP
Bilary stones, sludge or crystals EUS, MRCP, ERCP, Duodenal
aspiration with crystal
analysis
Congenital anomalies (pancreas EUS, MRCP, ERCP
divisum, annular pancreas,
anomalous pancreatobiliary
junction, choledochocele)
Chronic pancreatitis EUS, MRCP, ERCP, Secretin
stimulation test
Genetic Genetic analysis of the cystic
fibrosis gene, trypsin gene,
and pancreatic secretory
trypsin inhibitor gene
Neoplasm (pancreatic, EUS, MRCP, ERCP
ampullary)
Sphincter of Oddi dysfunction ERCP with sphincter of Oddi
manometry
protease inhibitor renders the pancreas more vulnerable
to injury.32 More recent studies have found that the
incidence of ␣1-antitrypsin mutations was similar in
patients with IAP and normal controls.33
In general, the role of genetic testing in IAP is con-
troversial. Many of these mutations cannot even be mea-
sured by commercially available techniques (eg, most
commercially available kits measure less than 100 of the
known 1200 CFTR mutations). In addition, diagnosing
these genetic disorders will add little to patient manage-
ment since no specific therapy is available. Similarly,
inadvertent disclosure of the results of genetic testing
might have significant negative effects on the patient and
the ability to obtain health insurance. On the other hand,
one could argue that the identification of an underlying
genetic cause may obviate the need for further testing,
might allow more informed family planning, and might
allow better surveillance for complications including
pancreatic cancer. At the moment, the lack of commer-
cially available techniques makes genetic testing a moot
point. In the future, however, it is likely this will assume
a more prominent role in the evaluation of patients with
IAP. The decision to pursue genetic testing is one that
should only be made with the advice and involvement of
an experienced genetic counselor.
At the current time, microlithiasis is diagnosed by
bile analysis. The procedure requires stimulation with
cholecystokinin, followed by aspiration of bile in the
duodenum via a designated duodenal tube or an endo-
scope or by collection of pure bile via a biliary catheter at
the time of ERCP. Although perhaps technically differ-
ent, the terms microlithiasis, biliary sludge, and biliary
760 DRAGANOV AND FORSMARK
crystals are often used interchangeably. Microlithiasis
refers to stones of ⬍ 3 mm. Biliary sludge is a suspension
of crystals, mucin, glycoproteins, cellular debris, and
proteinaceous material. Finally, the term biliary crystals
refers to isolated crystals of calcium bilirubinate, calcium
carbonate, or cholesterol monohydrate. The high preva-
lence of biliary crystals in patients with IAP suggests
that they are the most common etiology.26,21 The opti-
mal method to detect biliary crystals is yet to be deter-
mined. The sensitivity of duodenal bile aspiration via a
duodenal tube is around 65% with specificity of 94%–
100%.21,25 Several important issues limit the use of bile
analysis. The test is not appropriate in those who
have had previous cholecystectomy. Many patients
(29%–34%) with gallstones (who all should be expected
to have microlithiasis or crystals) have a negative bile
analysis.21,24,25 The technique is not standardized, and in
particular the quantity of crystals needed to define a
positive result differs among institutions (but most be-
lieve that the presence of even a small number of crystals
is abnormal).34 Finally, the procedure is only available at
tertiary institutions. The use of bile analysis remains
controversial and poorly standardized, and further re-
search is needed.35
The measurement of tumor markers (particularly CA
19-9) may be considered in patients with IAP who seem
to be at highest risk for pancreatic cancer (age ⬎ 40,
positive family history, tobacco use). The accuracy of this
approach is unknown but is likely to be of exceedingly
low sensitivity.
Some patients with an attack of IAP actually have
chronic pancreatitis. This may only become apparent
after prolonged follow-up. The identification of this
group of patients is difficult but direct pancreatic func-
tion testing (secretin or CCK stimulation test), endo-
scopic-based pancreatic function tests, and possibly EUS
may identify this group of patients.36,37 This type of
testing is rarely considered after a single episode of IAP
but might be considered after multiple attacks.38 Auto-
immune pancreatitis is a benign disease characterized by
irregular narrowing of the pancreatic duct, swelling of
parenchyma, lymphoplasmacytic infiltration and fibrosis,
and a favorable response to corticosteroid treatment. In
this condition, the whole pancreas is diffusely affected,
however, a few cases with focal mass lesions mimicking
pancreatic adenocarcinoma are reported.39,40 Patients
with autoimmune pancreatitis have high antinuclear an-
tibody and serum IgG4 concentrations, providing a use-
ful means of distinguishing this disorder from other
diseases of the pancreas or biliary tract.41,42 We believe
that since autoimmune pancreatitis has specific therapy
checking antinuclear antibody and serum IgG4 concen-
GASTROENTEROLOGY Vol. 128, No. 3
trations should be considered in selected patients with
idiopathic AP.
MRCP and EUS. MRCP and EUS can detect
many of the potential causes of AP (Table 3). MRCP and
EUS are particularly useful in detecting bile duct
stones.43–55 The sensitivity and specificity are excellent,
ranging from 90% to 100%. In addition MRCP and
EUS can detect pancreatic or ampullary tumors, chole-
dochal cysts, chronic pancreatitis, pancreas divisum, an-
nular pancreas, and anomalous pancreatico-biliary junc-
tion. MRCP after secretin stimulation can also diagnose
pancreatic duct disruption as seen after abdominal trau-
ma.15 EUS has also been able to detect microlithiasis and
biliary sludge with high accuracy (perhaps higher than
bile analysis).49,50 As an added benefit, bile can be col-
lected from the duodenum after cholecystokinin stimu-
lation through the EUS scope. In our institution, EUS is
the preferred test for evaluating patients with IAP. De-
pending on local expertise and availability of EUS and
high-quality MRI with MRCP, one or the other may be
preferred.
ERCP. The use of ERCP is supported by the
capability to establish the etiology and at the same time
to provide definitive therapy for a number of the causes
of IAP. ERCP when combined with ancillary techniques
can be a very potent tool in detecting structural or
functional abnormalities of the biliary tree and pancreas.
At the time of the endoscopic portion of the procedure
ampullary abnormalities such as tumors can be easily
identified. Cholangiography and pancreatography can
show bile duct stones, chronic pancreatitis, pancreatic or
biliary neoplasms, and congenital abnormalities such as
pancreas divisum, annular pancreas, choledochal cysts,
and anomalous pancreatobiliary junction. The diagnostic
ability of ERCP is further expanded if sphincter of Oddi
manometry (SOM) and bile aspiration for crystal analysis
is added to the diagnostic armamentarium. The diagnos-
tic yield of ERCP with SOM and bile crystal analysis in
patients with IAP varies among studies but in most cases
is high and ranges from 70%– 85%.16 –21,56 –58 The three
most common diagnoses by far are sphincter of Oddi
dysfunction, biliary macrolithiasis (stones), and biliary
microlithiasis (crystals).
The main controversy behind the use of ERCP stems
from the high complication rate associated with the
procedure. Post-ERCP pancreatitis is the main drawback
of ERCP and occurs on average in 5% of the patients. Of
particular concern is that in patients with IAP the rate of
post-ERCP pancreatitis is much higher. Patients with
prior history of pancreatitis have 12.5% risk of post-
ERCP pancreatitis. The two largest prospective studies
have found that the risk is even higher (21%–23%) in
March 2005
patients with suspected SOD undergoing SOM.59,60
Complicating the matter still further, normal values for
SOM are not available for patients with a gallbladder in
situ. A vast number of editorials, expert opinions, and
consensus statements have been published regarding the
role of ERCP in general and in the management of IAP
in particular.35,61,62 Opinions vary.
Based on our interpretation of the available literature
we recommend the following algorithm: ERCP should
be avoided in patients with a single mild episode of IAP,
unless there is no access to EUS or high-quality MRCP.
ERCP can be considered in patients with two or more
attacks of IAP or if the initial episode was severe. In these
patients, MRCP or EUS should be performed first. If the
MRCP or EUS define the cause of the recurrent pancre-
atitis, then appropriate targeted treatment should be
undertaken. If the MRCP or EUS is negative, then ERCP
should be considered, with the capability of SOM and
bile analysis for crystals. ERCP without concomitant
SOM and bile analysis is not usually justifiable. The use
of empiric sphincterotomy without first documenting
elevated sphincter of Oddi pressure or the presence of
biliary crystals is to be discouraged.
Recommended Management
Strategy
In our patient the initial evaluation consisting of
history, physical examination, focused laboratory testing,
US, and CT is unrevealing for the etiology of AP. At this
point the no further testing strategy is a viable option
since the patient has had a single mild attack of AP and
is at relatively low risk for pancreatic cancer (age ⬍ 40,
no use of tobacco, no family history of pancreatic cancer).
However, in this case a limited specialized testing could
also be considered. Based on the high diagnostic yield
and safety, our recommendation in this patient is to
perform EUS. EUS will be able to detect or exclude a
large number of potential etiologic causes for this episode
of IAP. If the EUS exam is unrevealing, at the time of the
same procedure we would administer cholecystokinin
with aspiration of bile via the echoendoscope. If the EUS
followed by bile analysis is negative an expectant ap-
proach should be taken. If the patient develops a second
attack of IAP, empiric laparoscopic cholecystectomy is
quite reasonable, although one could also consider ERCP
with SOM.
Conclusion
A detailed history and physical examination along
with focused laboratory testing and routine radiological
evaluation consisting of US and/or CT can detect the
IDIOPATHIC PANCREATITIS 761
underlying etiology of acute pancreatitis in approxi-
mately 80% of the patients. If this initial investigation is
unrevealing, the patient is classified as having idiopathic
acute pancreatitis. Further advanced evaluation is defi-
nitely indicated in patients with a severe initial attack of
AP or with two or more attacks. Advanced evaluation
may consist of one or more the following: specialized
laboratory studies, MRCP, EUS, and ERCP with SOM.
Based on local expertise MRCP or EUS should be con-
sidered for the initial step in this specialized evaluation
because of their safety and high diagnostic yield. If the
MRCP or EUS is negative, then either empiric cholecys-
tectomy or ERCP with SOM and bile analysis for crystals
should be considered.
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Address requests for reprints to: Chris E. Forsmark, MD, University of
Florida, Box 10021, Room HD-602, 1600 SW Archer Road, Gainesville,
Florida 32610-0214. e-mail: forsmce@medicine.ufl.edu; fax: (352)
392-3618.