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Idiopathic Acute Recurrent PancreatitisMichael J. Levy, M.D., and Joseph E. Geenen, M.D.The Mayo Clinic, Rochester, Minnesota; and The Pancreatic Biliary Center, St. Lukes Medical Center,Milwaukee, Wisconsin
Acute recurrent pancreatitis (ARP) results most commonlyfrom alcohol abuse or gallstone disease. Initial evaluationfails to detect the cause of ARP in 1030% of patients, andas a result the diagnosis of idiopathic ARP is given. Inthese patients, a more extensive evaluation including spe-cialized labs, ERCP, endoscopic ultrasound, or magneticresonance cholangiopancreatography typically leads to adiagnosis of microlithiasis, sphincter of Oddi dysfunction,or pancreas divisum. Less commonly, hereditary pancreati-tis, cystic fibrosis, a choledochocele, annular pancreas, ananomalous pancreatobiliary junction, pancreatobiliary tu-mors, or chronic pancreatitis are diagnosed. Determining theetiology is important, as it helps to direct therapy, limitsfurther unnecessary evaluation, and may improve a patientslong term prognosis. (Am J Gastroenterol 2001;96:25402555. 2001 by Am. Coll. of Gastroenterology)
Acute pancreatitis is an inflammatory process of the pan-creas that can affect peripancreatic tissues and distant sites.An etiology can be found in most patients after an attack ofacute pancreatitis, with gallstone disease and alcohol abusemost often implicated (Table 1). When patients have morethan one clinical episode of acute pancreatitis they are giventhe diagnosis of acute recurrent pancreatitis (ARP). Mostcauses of acute pancreatitis can lead to recurrent disease ifthe underlying factor remains uncorrected (1, 2).
The etiology of ARP is found in 7090% of patients afteran initial evaluation, which includes a thorough history,physical exam, routine labs, and transabdominal ultrasoundor CT (Table 2). In the 1030% of patients in whom theinitial evaluation fails to reveal an etiology, the diagnosis ofidiopathic ARP (IARP) is applied (1, 35). The extent of theevaluation impacts the frequency with which an etiologycan be found, and in turn how often the labelidiopathic canbe applied. Evaluation and therapy is important because50% of untreated patients with IARP experience recurrentepisodes that may lead to chronic pancreatitis (1, 6).
INITIAL EVALUATION OF ACUTE PANCREATITIS
Acute pancreatitis is diagnosed in the proper clinical settingwith the aid of laboratory values and imaging studies. Pa-
tients may present with acute epigastric pain, nausea, vom-iting, fever, and tachycardia. Laboratory analysis usuallyreveals elevated pancreatic enzymes and leukocytosis. Ab-dominal ultrasound and CT help support the diagnosis andexclude other causes. After confirmation of the presence ofacute pancreatitis, the focus shifts to determining the etiol-ogy. The initial evaluation includes a search for evidence ofalcohol abuse, drug-induced pancreatitis, and a family his-tory of pancreatitis, and other clues that may suggest theorigin.
The serum amylase level is used to help establish thediagnosis of pancreatitis and may be predictive of the un-derlying pathology. Pancreatitis resulting from gallstones,microlithiasis, or drugs is typically associated with a greaterelevation in amylase than lipase (7, 8). The amylase level, ascompared to lipase, tends to be lower in alcoholic pancre-atitis, hypertriglyceridemia-induced pancreatitis, neoplasia,and chronic pancreatitis (7, 8). Lipase elevation is morespecific for pancreatitis than amylase, and the level remainselevated longer, but the level is not predictive of the etiology(9). The ratio of lipase to amylase may help distinguishalcoholic from nonalcoholic pancreatitis, with an increasedratio suggesting alcohol-induced disease (7, 8). Of note, theamylase and lipase levels do not correlate with diseaseseverity and they are not useful for determining prognosis.
Liver function tests are routinely measured and may beelevated because of biliary obstruction resulting from gall-stones, microlithiasis, a choledochocele, neoplasia of theampulla or pancreas, or sphincter of Oddi dysfunction(SOD). Liver function tests may also increase as a result ofpancreatic head edema, inflammation, or pseudocyst forma-tion. A 3-fold or greater increase in the ALAT level isgenerally regarded as the best indicator of gallstone-inducedpancreatitis (10). One study, however, noted that the bestindicator of bile duct stones is a serum total bilirubin 1.35mg/dl on the second day of hospitalization (11). Although itis unclear which laboratory parameter is the most predictive,both may be used to help assess the presence of gallstone-induced pancreatitis in an individual patient. Metaboliccauses of pancreatitis should be excluded by checking theserum calcium and triglyceride levels. These values shouldbe measured soon after admission, or well after resolution ofthe pancreatitis, because of the drop in calcium and triglyc-eride levels that can occur during hospitalization (12).
Transabdominal ultrasound is a simple, inexpensive, and
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 9, 2001 2001 by Am. Coll. of Gastroenterology ISSN 0002-9270/01/$20.00Published by Elsevier Science Inc. PII S0002-9270(01)02661-2
highly sensitive procedure for evaluating the biliary tract(13). CT more accurately delineates the pancreas and mayalso help identify the cause, assess the severity, and detectcomplications of pancreatitis (14). Some recommend per-forming CT only when the first attack is severe, when thecourse is complicated, or in the elderly. Patients not scannedduring the first episode are generally scanned with theirsecond attack regardless of age or disease severity. How-ever, we believe that the yield is great enough to justify a CTin all patients during their first episode.
The extent of evaluation required before conferring thediagnosis of IARP varies among studies (3, 15, 16). Thepurist would demand a complete and exhaustive workupbefore diagnosis. However, most use this diagnosis when amore limited evaluation, as detailed above, fails to reveal anetiology. A more extensive evaluation may include special-ized labs, ERCP, endoscopic ultrasound (EUS), and mag-netic resonance cholangiopancreatography (MRCP) (Table3). This additional workup usually leads to the diagnosis ofmicrolithiasis, SOD, or pancreas divisum (Fig. 1) (1, 2, 4).Other causes such as hereditary pancreatitis (17), cysticfibrosis (18), a choledochocele (19), annular pancreas (20),an anomalous pancreatobiliary junction (21), pancreatobili-ary tumors (22), and chronic pancreatitis (23) may be foundas well. When this more extensive evaluation fails to revealan etiology, then the diagnosis of true IARP (TIARP) maybe assigned. This article will focus on many of the disordersassociated with IARP and outline diagnostic and therapeuticoptions.
MICROLITHIASIS (BILIARY SLUDGE)
Although technically different, the terms microlithiasis andbiliary sludge are often used interchangeably. Microlithiasisrefers to stones of 3 mm in diameter, whereas biliarysludge is a suspension of crystals, mucin, glycoproteins,cellular debris, and proteinaceous material (24). The crystalsare composed of calcium bilirubinate, calcium carbonate, orcholesterol monohydrate (5, 25). Microlithiasis is frequently
Table 1. (continued)
Primary sclerosing cholangitisRenal disease
Chronic renal failureDialysis related
Sphincter of Oddi dysfunctionToxin
Organophosphate insecticidesScorpion bite
Polyarteritis nodosaSystemic lupus erythematosus
Table 1. Etiologies of Acute Recurrent Pancreatitis
AlcoholBiliary calculous disease
Macrolithiasis (bile duct stone)Microlithiasis (sludge)
Biliary cystic diseaseCholedochal cystCholedochocele/duplication cyst
Congenital anomalyAnnular pancreasAnomalous pancreatobiliary junctionPancreas divisum
Duodenal obstructionAfferent limb obstructed (Billroth II)AtresiaCrohns diseaseDiverticulum
DrugsAcetaminophenAzathioprineDidanosineErythromycinEstrogenFurosemideHistamine-2 receptor antagonistsMercaptopurineMethyldopaMetronidazoleNitrofurantoinNonsteroidal anti-inflammatory agentsPentamidineTetracyclineValproic acid
Genetic-1-antitrypsin deficiencyCystic fibrosisHereditary pancreatitis
BacterialCampylobacter jejuniLegionellaLeptospirosisMycobacterium avium complexMycobacterium tuberculosisMycoplasma
Parasites/wormsAscaris lumbricoidesClonorchis sinensisCryptosporidiumMicrosporidium
ViralCoxsackievirusCytomegalovirusEcho virusEpstein-Barr virusHepatitis (A, B, C) virusHIVMumps virusRubella virusVaricella virus
2541AJG September, 2001 Idiopathic Acute Recurrent Pancreatitis
implicated as the cause of IARP. However, some believethat microlithiasis does not cause pancreatitis, but insteadindicates the prior presence of larger common bile ductstones that precipitated the pancreatitis. In fact, pancreatitismay induce sludge formation by diminishing gallbladdercontractility, thereby leading to some uncertainty regardingthe causal relationship between sludge and pancreatitis.Although some studies have detected microlithiasis in asfew as 7% of patients with IARP (1), others have foundevidence of microlithiasis in approximately two thirds ofpatients (5, 26).
Microlithiasis may lead to pancreatitis through severalmechanisms. Small stones may transiently impact the pa-pilla leading to pancreatic duct obstruction and eventualpancreatitis (27). Repeated exposure to microlithiasis maylead to papillary stenosis and SOD, both of which areassociated with pancreatitis (28).
The optimum method of d