Idiopathic Acute Recurrent Pancreatitis Michael J

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THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 9, 2001 © 2001 by Am. Coll. of Gastroenterology ISSN 0002-9270/01/$20.00 Published by Elsevier Science Inc. PII S0002-9270(01)02661-2 CLINICAL REVIEWS Idiopathic Acute Recurrent Pancreatitis Michael J. Levy, M.D., and Joseph E. Geenen, M.D. The Mayo Clinic, Rochester, Minnesota; and The Pancreatic Biliary Center, St. Luke’s Medical Center, Milwaukee, Wisconsin

ABSTRACT tients may present with acute epigastric pain, nausea, vomiting, fever, and tachycardia. Laboratory analysis usually Acute recurrent pancreatitis (ARP) results most commonly reveals elevated pancreatic enzymes and leukocytosis. Ab- from alcohol abuse or gallstone disease. Initial evaluation dominal ultrasound and CT help support the diagnosis and fails to detect the cause of ARP in 10–30% of patients, and exclude other causes. After confirmation of the presence of as a result the diagnosis of “idiopathic” ARP is given. In acute pancreatitis, the focus shifts to determining the etiol- these patients, a more extensive evaluation including spe- ogy. The initial evaluation includes a search for evidence of cialized labs, ERCP, endoscopic ultrasound, or magnetic alcohol abuse, drug-induced pancreatitis, and a family his- resonance cholangiopancreatography typically leads to a tory of pancreatitis, and other clues that may suggest the diagnosis of microlithiasis, sphincter of Oddi dysfunction, origin. or pancreas divisum. Less commonly, hereditary pancreati- The serum amylase level is used to help establish the tis, cystic fibrosis, a choledochocele, annular pancreas, an diagnosis of pancreatitis and may be predictive of the un- anomalous pancreatobiliary junction, pancreatobiliary tu- derlying pathology. Pancreatitis resulting from gallstones, mors, or chronic pancreatitis are diagnosed. Determining the microlithiasis, or drugs is typically associated with a greater etiology is important, as it helps to direct therapy, limits elevation in amylase than lipase (7, 8). The amylase level, as further unnecessary evaluation, and may improve a patient’s long term prognosis. (Am J Gastroenterol 2001;96: compared to lipase, tends to be lower in alcoholic pancre- 2540–2555. © 2001 by Am. Coll. of Gastroenterology) atitis, hypertriglyceridemia-induced pancreatitis, neoplasia, and chronic pancreatitis (7, 8). Lipase elevation is more specific for pancreatitis than amylase, and the level remains INTRODUCTION elevated longer, but the level is not predictive of the etiology Acute pancreatitis is an inflammatory process of the pan- (9). The ratio of lipase to amylase may help distinguish creas that can affect peripancreatic tissues and distant sites. alcoholic from nonalcoholic pancreatitis, with an increased An etiology can be found in most patients after an attack of ratio suggesting alcohol-induced disease (7, 8). Of note, the acute pancreatitis, with gallstone disease and alcohol abuse amylase and lipase levels do not correlate with disease most often implicated (Table 1). When patients have more severity and they are not useful for determining prognosis. than one clinical episode of acute pancreatitis they are given Liver function tests are routinely measured and may be the diagnosis of acute recurrent pancreatitis (ARP). Most elevated because of biliary obstruction resulting from gall- causes of acute pancreatitis can lead to recurrent disease if stones, microlithiasis, a choledochocele, neoplasia of the the underlying factor remains uncorrected (1, 2). ampulla or pancreas, or sphincter of Oddi dysfunction The etiology of ARP is found in 70–90% of patients after (SOD). Liver function tests may also increase as a result of an initial evaluation, which includes a thorough history, pancreatic head edema, inflammation, or pseudocyst forma- physical exam, routine labs, and transabdominal ultrasound tion. A 3-fold or greater increase in the ALAT level is or CT (Table 2). In the 10–30% of patients in whom the generally regarded as the best indicator of gallstone-induced initial evaluation fails to reveal an etiology, the diagnosis of pancreatitis (10). One study, however, noted that the best idiopathic ARP (IARP) is applied (1, 3–5). The extent of the indicator of bile duct stones is a serum total bilirubin Ͼ 1.35 evaluation impacts the frequency with which an etiology mg/dl on the second day of hospitalization (11). Although it can be found, and in turn how often the label idiopathic can is unclear which laboratory parameter is the most predictive, be applied. Evaluation and therapy is important because both may be used to help assess the presence of gallstone- Ͼ50% of untreated patients with IARP experience recurrent induced pancreatitis in an individual patient. Metabolic episodes that may lead to chronic pancreatitis (1, 6). causes of pancreatitis should be excluded by checking the serum calcium and triglyceride levels. These values should INITIAL EVALUATION OF ACUTE PANCREATITIS be measured soon after admission, or well after resolution of the pancreatitis, because of the drop in calcium and triglyc- Acute pancreatitis is diagnosed in the proper clinical setting eride levels that can occur during hospitalization (12). with the aid of laboratory values and imaging studies. Pa- Transabdominal ultrasound is a simple, inexpensive, and AJG – September, 2001 Idiopathic Acute Recurrent Pancreatitis 2541

Table 1. Etiologies of Acute Recurrent Pancreatitis Table 1. (continued) Alcohol Pancreatitis-related complications Biliary calculous disease Fistula/ascites Macrolithiasis (bile duct stone) Pseudocyst Microlithiasis (sludge) Stone Biliary cystic disease Stricture Choledochal cyst Primary sclerosing cholangitis Choledochocele/duplication cyst Renal disease Congenital anomaly Chronic renal failure Annular pancreas Dialysis related Anomalous pancreatobiliary junction Sphincter of Oddi dysfunction Pancreas divisum Toxin Duodenal obstruction Organophosphate insecticides Afferent limb obstructed (Billroth II) Scorpion bite Atresia Tropical Crohn’s disease Vasculitis Diverticulum Polyarteritis nodosa Drugs Systemic lupus erythematosus Acetaminophen Azathioprine Didanosine highly sensitive procedure for evaluating the biliary tract Erythromycin (13). CT more accurately delineates the pancreas and may Estrogen Furosemide also help identify the cause, assess the severity, and detect Histamine-2 receptor antagonists complications of pancreatitis (14). Some recommend per- Mercaptopurine forming CT only when the first attack is severe, when the Methyldopa course is complicated, or in the elderly. Patients not scanned Metronidazole Nitrofurantoin during the first episode are generally scanned with their Nonsteroidal anti-inflammatory agents second attack regardless of age or disease severity. How- Pentamidine ever, we believe that the yield is great enough to justify a CT Tetracycline in all patients during their first episode. Valproic acid The extent of evaluation required before conferring the Genetic ␣-1-antitrypsin deficiency diagnosis of IARP varies among studies (3, 15, 16). The Cystic fibrosis purist would demand a complete and exhaustive workup Hereditary pancreatitis before diagnosis. However, most use this diagnosis when a Idiopathic more limited evaluation, as detailed above, fails to reveal an Infection etiology. A more extensive evaluation may include special- Bacterial Campylobacter jejuni ized labs, ERCP, endoscopic ultrasound (EUS), and mag- Legionella netic resonance cholangiopancreatography (MRCP) (Table Leptospirosis 3). This additional workup usually leads to the diagnosis of Mycobacterium avium complex microlithiasis, SOD, or pancreas divisum (Fig. 1) (1, 2, 4). Mycobacterium tuberculosis Mycoplasma Other causes such as hereditary pancreatitis (17), cystic Parasites/worms fibrosis (18), a choledochocele (19), annular pancreas (20), Ascaris lumbricoides an anomalous pancreatobiliary junction (21), pancreatobili- Clonorchis sinensis ary tumors (22), and chronic pancreatitis (23) may be found Cryptosporidium as well. When this more extensive evaluation fails to reveal Microsporidium Viral an etiology, then the diagnosis of “true” IARP (TIARP) may Coxsackievirus be assigned. This article will focus on many of the disorders Cytomegalovirus associated with IARP and outline diagnostic and therapeutic Echo virus options. Epstein-Barr virus Hepatitis (A, B, C) virus HIV MICROLITHIASIS (BILIARY SLUDGE) Mumps virus Rubella virus Although technically different, the terms microlithiasis and Varicella virus biliary sludge are often used interchangeably. Microlithiasis Metabolic Ͻ Hypercalcemia refers to stones of 3 mm in diameter, whereas biliary Hyperlipidemia sludge is a suspension of crystals, mucin, glycoproteins, Neoplasm cellular debris, and proteinaceous material (24). The crystals Benign are composed of calcium bilirubinate, calcium carbonate, or Malignant cholesterol monohydrate (5, 25). Microlithiasis is frequently 2542 Levy and Geenen AJG – Vol. 96, No. 9, 2001

Table 2. Initial Evaluation of Acute Recurrent Pancreatitis Table 3. Further Evaluation of Idiopathic Acute Recurrent Pancreatitis Parameter Potential Etiology/Diagnosis History Parameter Potential Etiology/Diagnosis Alcohol abuse Alcohol Laboratory Drug intake Drugs ␣-1-antitrypsin phenotype ␣-1-antitrypsin deficiency Family history Hereditary CFTR gene analysis Cystic fibrosis Laboratory Sweat electrolytes Cystic fibrosis Amylase and lipase (Ͼ5ϫ) Drugs Trypsin gene studies Hereditary pancreatitis Macrolithiasis (bile duct stone) Tumor marker (CA 19-9) Neoplasm Microlithiasis (sludge) Duodenal aspiration Microlithiasis (Ͻ5ϫ) Alcohol ERCP Chronic pancreatitis Appearance (bulging Choledochocele Hyperlipemia ampulla) Neoplasm Duodenal duplication cyst Calcium Hypercalcemia Papillitis Liver function tests Choledochocele Stone (impacted) Macrolithiasis (bile duct stone) Tumor Microlithiasis (sludge) Appearance (duct Annular pancreas Neoplasm (ampulla, pancreas) abnormality) Pancreatic head inflammation Anomalous pancreatobiliary Pancreatic head pseudocyst junction Sphincter of Oddi dysfunction Choledochal cyst Triglycerides Hypertriglyceridemia Chronic pancreatitis Radiographs (complications) Ultrasound (transabdominal) Chronic pancreatitis Macrolithiasis (bile duct stone) Choledochal cyst Microlithiasis (sludge) Choledochocele Pancreas divisum Macrolithiasis (bile duct stone) Bile duct aspiration Microlithiasis Microlithiasis (sludge) Brush cytology/biopsy Neoplasm Neoplasm (ampulla, pancreas) Intraductal secretin test Chronic pancreatitis CT Annular pancreas Minor papilla cannulation Pancreas divisum Choledochal cyst Sphincter of Oddi Sphincter of Oddi dysfunction Choledochocele manometry Chronic pancreatitis Endoscopic ultrasound Macrolithiasis (bile duct stone) Appearance/image Anomalous pancreatobiliary Microlithiasis (sludge) Neoplasm (ampulla, pancreas) junction Chronic pancreatitis Macrolithiasis (bile duct stone) Microlithiasis (sludge) implicated as the cause of IARP. However, some believe Neoplasm (ampullary and that microlithiasis does not cause pancreatitis, but instead pancreatic) Pancreas divisum indicates the prior presence of larger common bile duct Fine needle aspirate Neoplasm stones that precipitated the pancreatitis. In fact, pancreatitis Secretin stimulated Sphincter of Oddi dysfunction may induce sludge formation by diminishing gallbladder MRI/MRCP contractility, thereby leading to some uncertainty regarding Appearance/image Annular pancreas the causal relationship between sludge and pancreatitis. Anomalous pancreatobiliary junction Although some studies have detected microlithiasis in as Choledochocele few as 7% of patients with IARP (1), others have found Chronic pancreatitis evidence of microlithiasis in approximately two thirds of Macrolithiasis (bile duct stone) patients (5, 26). Microlithiasis (sludge) Microlithiasis may lead to pancreatitis through several Neoplasm (ampullary and mechanisms. Small stones may transiently impact the pa- pancreatic) Pancreas divisum pilla leading to pancreatic duct obstruction and eventual pancreatitis (27). Repeated exposure to microlithiasis may lead to papillary stenosis and SOD, both of which are about 66% (30, 31). ERCP is more invasive, but has a associated with pancreatitis (28). sensitivity of about 85% (25, 29). During ERCP, the com- The optimum method of detecting microlithiasis is yet to mon bile duct is directly aspirated for bile. Cholecystokinin be established. Transabdominal ultrasound is a noninvasive is commonly administered before duodenal drainage or study with a sensitivity of about 50% (5, 29). However, ERCP, to enhance gallbladder contractility and improve the repeat examination may improve the yield. Duodenal bile yield. In most centers, collected bile is centrifuged at 2000 aspiration is an invasive procedure that has a sensitivity of revolutions/min for 10 min; the sediment is warmed to 37°C AJG – September, 2001 Idiopathic Acute Recurrent Pancreatitis 2543

Figure 2. Sludge. EUS (radial scanning) demonstrating the presence of gallbladder sludge in a patient referred for evaluation of IARP. Figure 1. Pathological processes associated with IARP. Image courtesy of Patsy Bryan. in roughly one third of these patients (38, 39). SOD causes diminished transphincteric flow of bile or pancreatic juice because of organic obstruction (stenosis) or functional ob- and then examined by polarized microscopy. The quantity struction (dysmotility). This may cause pancreatitis by pro- of crystals needed to define a positive result differs among moting reflux of bile into the pancreatic duct or by obstruct- institutions, but most believe that the presence of even a ing pancreatic duct outflow (1, 27). small number of crystals is abnormal. EUS is increasingly Patients with SOD are classified as having either biliary being used because it offers the greatest diagnostic sensi- type or pancreatic type disease (Table 4) (40, 41). Subclas- tivity (Fig. 2) (32, 33). The presence of microlithiasis may sifying (types I, II, and III) helps to predict the underlying also be noted at the time of MRCP (34). pathology. Type I disease usually results from stenosis, and Therapy for microlithiasis can significantly reduce the type III disease is typically a consequence of dysmotility risk of recurrent pancreatitis (5, 26). Several therapeutic (40, 41). Subclassifying also helps us to predict the likeli- options exist for microlithiasis. Laparoscopic cholecystec- hood of pain relief after therapy, with the highest response tomy is nearly always curative and generally considered the rate occurring in patients with type I disease. procedure of choice (5, 26). ERCP with sphincterotomy Sphincter of Oddi manometry (SOM) is the gold standard (incision of the bile duct sphincter) is indicated in high for diagnosing SOD. SOM employs a water-perfused cath- operative risk patients (35, 36). A low-fat diet and ursode- eter system, which is inserted endoscopically into the com- oxycholic acid are acceptable alternatives in high surgical mon bile duct or pancreatic duct, to measure the sphincter risk patients; however, long term therapy is required (26, 37). Table 4. Sphincter of Oddi Dysfunction (Geenen & Hogan Classification) Biliary Type Pancreatic Type SPHINCTER OF ODDI DYSFUNCTION Type I Type I Biliary-type pain Pancreatic-type pain The sphincter of Oddi is a 5- to 15-mm-long fibromuscular LFT elevated Amylase/lipase elevation sheath that encircles the terminal common bile duct, pan- CBD dilation PD dilation creatic duct, and common channel. This sphincter regulates Delayed drainage Delayed drainage the flow of bile and pancreatic juice into the duodenum, Type II Type II Biliary-type pain Pancreatic-type pain inhibits reflux of duodenal contents into the common bile One or two of above criteria One or two of above criteria duct and pancreatic duct, and promotes gallbladder filling Type III Type III with bile. Biliary-type pain only Pancreatic-type pain only SOD is a frequent and treatable cause of IARP and is seen CBD ϭ common bile duct; LFT ϭ liver function test; PD ϭ pancreatic duct. 2544 Levy and Geenen AJG – Vol. 96, No. 9, 2001 pressure. The diagnosis is established by finding a hyper- tensive sphincter of Oddi pressure (Ͼ40 mm Hg) during manometry (40). Because of the risk of pancreatitis, SOM is reserved for patients with clinically significant or disabling symptoms. SOM is only performed if sphincter ablation is planned when confirming the diagnosis. This procedure is unnecessary and empirical therapy is reasonable in type I disease because of the prevalence of SOD in this subset (42). In our opinion, SOM is mandatory in type II and III disease because of the lower incidence of SOD in these patients. Noninvasive therapies for SOD include a low-fat diet, analgesics, anticholinergics, calcium channel blockers, and nitrates. Although these noninvasive therapies may help a minority of patients, most believe them to be of limited utility in the management of SOD (43, 44). Invasive therapies include endoscopic sphincterotomy (45, 46), pancreatic duct stent placement (47, 48), and surgical sphincteroplasty (49, 50). Intrasphincteric botulinum toxin (51) or nitric oxide (52) injection and balloon dilation (53) are no longer performed because they have a limited efficacy and fre- Figure 3. Pancreas divisum. Contrast injection into the major pa- quent, often severe complications. pilla reveals a small ventral pancreatic duct in a patient with pancreas divisum who presented with recurrent episodes of pan- The use of pancreatic duct stenting for SOD has not been creatitis. Image courtesy of Dr. Todd H. Baron. well studied, and available results have been disappointing. Stent placement may offer short term relief of symptoms and help to predict those most likely to benefit from endo- PANCREAS DIVISUM scopic sphincterotomy (54). However, because of its lack of long term efficacy and high rate of complications, pancreatic Pancreas divisum is the most common congenital malfor- duct stent therapy is not recommended for these patients mation of the pancreas, effecting 5–8% of the population (55). (60, 61). Normally, in the sixth to seventh weeks of gesta- Endoscopic sphincterotomy is the therapy of choice and tion, the ventral pancreatic bud and bile duct rotate 180° is believed to decrease the risk of recurrent pancreatitis (1, counterclockwise around the foregut and line up caudal to 45). Biliary sphincterotomy effectively reduces the pancre- the dorsal pancreatic bud. The ventral and dorsal buds then atic sphincter pressure (38, 56) and leads to clinical im- fuse. As a result, the larger ventral duct (duct of Wirsung) provement in roughly 80% of patients (39). A lack of drains the majority of the pancreas through the major pa- improvement is noted when biliary sphincterotomy fails to pilla. The smaller dorsal duct (duct of Santorini) empties via ablate the pancreatic sphincter (57). In such cases, SOM is the smaller accessory (minor) papilla and has little influence on pancreatic drainage. repeated to record the pancreatic sphincter pressure and Pancreas divisum results when the embryological ventral direct further therapy. We favor initially cutting the biliary and dorsal ducts fail to fuse. As a result, the ventral duct sphincter and, only if pancreatitis recurs, then later cutting only drains the ventral pancreas. The majority of the pan- the pancreatic sphincter. Diagnostic and therapeutic inter- creas then drains via the dorsal duct through the minor ventions are directed toward the biliary sphincter because of papilla. In these patients, the minor papilla is often stenotic the greater risk of pancreatic sphincter manometry and ther- and therefore inhibits the flow of pancreatic juice (15, 61). apy. The complication rate of endoscopic sphincterotomy, Although it is controversial, most hold the belief that pan- when performed for SOD, is greater than for other indica- creas divisum is a common cause of IARP and is implicated tions (58). Pancreatitis develops in up to 25% of patients, in about 20% of patients (1, 60). The diagnosis is suspected with 1–3% developing severe pancreatitis. The risk of during ERCP, when injection of contrast media into the sphincterotomy is potentially ameliorated by placement of a major papilla reveals an absent or small ventral pancreatic pancreatic duct stent (59). duct (Fig. 3). The diagnosis is confirmed by minor papilla Surgical sphincteroplasty is an effective alternative (49, injection, which usually demonstrates a lack of communi- 50), but is more invasive and should only be performed cation between the dorsal and ventral ducts. However, at when endoscopic sphincterotomy fails. Pancreatic duct stent times the ventral and dorsal ducts do communicate via a thin placement has been less well studied, and most have noted filamentous channel (incomplete pancreas divisum). The equivocal or disappointing results (47, 48). clinical presentation and response to therapy for “incom- AJG – September, 2001 Idiopathic Acute Recurrent Pancreatitis 2545 plete” and “complete” pancreas divisum are identical (62). EUS or MRCP may also make the diagnosis (63–65). Endoscopic (66, 67) and surgical (68, 69) therapies decrease the rate of recurrent pancreatitis in 70–90% of patients with pancreas divisum and IARP when followed for up to 5 yr. Treatment is directed toward relieving outflow obstruction at the level of the minor papilla (67). Endo- scopic therapy is generally favored, with surgery reserved for those in whom endoscopic approaches fail. Endoscopic therapeutic options for the minor papilla include catheter dilation (70), stenting (47, 67), sphincterotomy (66, 71), or a combination of therapies. Catheter dilation and stenting alone (i.e., without minor papilla sphincterotomy) are generally ineffective and cannot be regarded as standard management. Importantly, pancreatic stents may induce ductal changes mimicking chronic pancreatitis, and therefore long term stenting should only be performed in a research setting in patients who are closely observed (72, 73). Minor papilla sphincterotomy is generally favored in these patients. When doing so, we recommend short term placement of a dorsal Figure 4. Hereditary pancreatitis. The pancreatogram of a patient with hereditary pancreatitis demonstrating a markedly dilated main pancreatic duct stent, which serves as a guide for the sphinc- pancreatic duct, dilated side branches, and pancreatic duct stones. terotomy and helps minimize the risk of complications (66). Image courtesy of Dr. Christopher J. Gostout. Use of an unflanged stent is important to encourage spon- taneous migration (74). with anastomosis of the pancreatic duct to the jejunum) may HEREDITARY (FAMILIAL) PANCREATITIS be beneficial. However, these therapies cannot be widely recommended because of absence of prospective studies Hereditary pancreatitis is a genetic disorder with an auto- demonstrating their ability to alter the disease course. A somal dominant means of transmission and an estimated conservative approach may be favored, given the tendency 80% penetrance (17). There is no gender predominance, and for improvement in severity and frequency of attacks over symptoms typically arise in childhood but may be delayed time. However, establishing the diagnosis may be important until the mid-30s (17). This disorder results from a mutation because of the potential impact on family planning and in the cationic trypsinogen gene located on chromosome because of the promise that gene therapy holds. It is impor- 7q35 (75). The anomaly involves an arginine to histidine tant that a patient receives counseling and gives informed substitution at amino acid 117 (R117H) or asparagine to consent before genetic testing for hereditary pancreatitis. isoleucine substitution at amino acid 21 (N21I) (76). This mutation leads to formation of an abnormal cationic CYSTIC FIBROSIS trypsinogen, impaired inactivation of trypsin, and continu- ous activation of digestive enzymes (77). It is theorized that Cystic fibrosis is a genetic disease with an autosomal reces- pancreatic autodigestion eventually leads to chronic pancre- sive means of transmission and is the most common disorder atitis. Patients may present with IARP, but commonly de- affecting the exocrine pancreas (79). It results from a mu- velop chronic pancreatitis with associated abdominal pain, tation in the cystic fibrosis transmembrane conductance diabetes mellitus, maldigestion, and steatorrhea (17). The regulator (CFTR) gene that encodes a cyclic adenosine lifetime risk of pancreatic cancer is roughly 40% and re- monophosphate–regulated ion channel protein that controls portedly 75% with paternal inheritance (78). the chloride channel (80). This mutation leads to diminished The diagnosis is easily made in patients developing pan- chloride transport across membranes, dehydrated viscous creatitis before 20 yr of age, with affected family members secretions, and organ dysfunction (81). This defect is linked over at least two generations, in the absence of an identifi- not only to sinusitis, nasal polyps, chronic bronchitis, and able cause. However, the diagnosis is sometimes made in male infertility, but to pancreatitis as well. patients without these features. ERCP may be normal early Most patients with cystic fibrosis develop pancreatic in- on, but in advanced disease typically reveals pancreatic duct sufficiency and malabsorption due to diminished pancreatic dilation, pancreatic duct stones, and pseudocysts (Fig. 4). bicarbonate and enzyme secretion (82). Acute recurrent or Therapy does not differ from other causes of acute and chronic pancreatitis develops in only 2% of patients, and chronic pancreatitis, nor does the management of compli- results from pancreatic duct occlusion by protein-rich acinar cations. Endoscopic clearance of pancreatic duct stones and secretions, acinar cell damage, and fibrosis (83). Interest- surgical pancreatic decompression (pancreaticojejunostomy ingly, patients who develop pancreatitis typically do not 2546 Levy and Geenen AJG – Vol. 96, No. 9, 2001 suffer from pancreatic insufficiency and do not manifest most of the phenotypic abnormalities. This is true because the genotypes that lead to acute or chronic pancreatitis cause only moderate loss of CFTR gene function (79). Over 800 mutations have been identified on the CFTR gene (84), which is located on chromosome 7q31 (80). Deletion of phenylalanine at amino acid 508 (⌬F508) is implicated in 70% of patients, with another 20 or so mutations accounting for most of the remaining cases (85). Ge- netic testing reveals that approximately 10–15% of patients with idiopathic pancreatitis are homozygous for a CFTR gene mutation (82, 86). Heterozygous CFTR mutations are seen in about 10–40% of patients with IARP or idiopathic chronic pancreatitis, but in Ͻ10% of persons with alcoholic pancreatitis and in the general population. Although they are implicated as a cause of pancreatitis by some, it is unclear if heterozygous CFTR mutations are linked with any other pathological states (82, 86). Heterozygous carriers may be at greater risk for pancreatitis in the presence of alcohol, drugs, or other risk factors. These patients may also possess another unidentified mutation in the corresponding allele. Diminished CFTR function may also result from impaired messenger RNA splicing. This occurs in patients with Figure 5. Choledochocele. Endoscopic appearance of a markedly enlarged major papilla in a patient presenting with several unex- a short polythymidine tract (5T), versus normal longer thy- plained episodes of acute pancreatitis. midine variants 7T and 9T, in intron 8 of the CFTR gene (87). The 5T variant is not associated with lung disease, but is associated with congenital absence of the vas deferens, diagnosis is usually confirmed by ERCP (90–93). Endo- and may be linked to idiopathic pancreatitis (87, 88). Cur- scopically, the papilla has a “bulging” appearance and feels rently, most laboratories are not routinely testing for the 5T soft (pillow sign) when pressure is applied with the catheter allele. tip (Fig. 5) (91). A duodenal duplication cyst, impacted Therapy does not differ from that for other causes of acute gallstone, papillitis, or tumor can mimic this appearance. and chronic pancreatitis. As with hereditary pancreatitis, consideration of the diagnosis is important for family plan- The clinical presentation and endoscopic appearance usually ning and because of the potential future role of gene therapy. make differentiation possible. Discovery of medications that enhance ductal bicarbonate “Unroofing” the choledochocele by endoscopic sphinc- secretion may one day prevent or slow the progression of terotomy is usually effective (91, 94), with few patients pancreatitis. requiring surgical sphincteroplasty (94). Surgery may be preferred for a large choledochocele because of the risk of bleeding with endoscopic therapy (90). CHOLEDOCHOCELE Cystic dilation may occur throughout the biliary system and can involve the extrahepatic and/or intrahepatic bile ducts. ANOMALOUS PANCREATOBILIARY JUNCTION Todani et al. (89), based on the location, first classified these An anomalous pancreatobiliary junction is defined by an cysts into five types. A type III cyst, or choledochocele, is abnormally long (Ͼ15 mm) common pancreatobiliary chan- a rare congenital or acquired condition in which the intra- mural segment of the distal pancreatobiliary ductal system is nel (92). This anomaly is associated with IARP, choledochal dilated and herniates into the duodenal lumen. They vary in cysts, cholangiocarcinoma, and gallbladder carcinoma (21, size from a few millimeters to several centimeters. Chole- 95). The sphincter does not separate the bile and pancreatic dochoceles are associated with biliary and pancreatic disor- ducts, and therefore pancreatic and bile juices may freely ders, including biliary colic, obstructive jaundice, and IARP flow between ducts and lead to pancreatitis. (19, 90). Of the five types, only type III cysts have been ERCP and injection of the major papilla reveal the long associated with IARP. Pancreatitis develops when the cyst common channel and simultaneous filling of the bile duct or its contents (sludge or stones) obstruct pancreatic duct and pancreatic duct. EUS or MRCP may also establish the outflow. diagnosis (93, 96, 97). Sphincter ablation by endoscopic Although abnormal laboratory values, transabdominal ul- sphincterotomy encourages normal flow of bile and pancre- trasound, CT, or MRCP may suggest a choledochocele, the atic juice and may decrease the risk of recurrent pancreatitis. AJG – September, 2001 Idiopathic Acute Recurrent Pancreatitis 2547

Figure 6. Annular pancreas. Pancreatogram outlining the pancreatic duct as it encircles the duodenum in a patient with multiple attacks of pancreatitis.

ANNULAR PANCREAS PANCREATOBILIARY TUMORS

Annular pancreas is a congenital anomaly that manifests as Five to seven percent of patients with pancreatobiliary tu- a band of pancreatic tissue partially or completely encircling mors, benign or malignant, present with IARP (22, 103, the duodenum, usually at the level of or just proximal to the 104). The presence of a neoplasia may be suggested by major papilla (92). This abnormality is detected in 1/7,000– significant weight loss, steatorrhea, radiological evidence of 20,000 autopsies (92, 98) and in about 1/1,500 ERCPs a solid or cystic pancreatic mass or ductal dilation, and (99–101). The defect occurs in utero when the ventral bud increased age. Although younger patients less commonly becomes fixed and fails to rotate with the duodenum (92). have a neoplasia, they are frequently affected by lesions Symptoms typically begin in childhood and develop as a such as islet cell tumors that are often amenable to curative result of duodenal obstruction, with intractable vomiting resection. Even the elderly may have potential curable le- most commonly noted (100, 101). Childhood disease is sions such as cystic neoplasms. Although pancreatic adeno- often associated with congenital anomalies such as Down’s carcinoma is most often implicated, these other tumors must syndrome, cardiac defects, tracheoesophageal fistula, Meck- be considered as well. el’s diverticulum, and imperforate anus (92, 100). Adults CT, magnetic resonance imaging (MRI), ERCP, and EUS may present with abdominal pain, IARP, chronic pancreati- are all useful for identifying pancreatobiliary neoplasms tis, peptic ulcer disease, or biliary obstruction (20, 101). (Fig. 7) (105–108). The extent of the evaluation is typically Although barium x-ray, CT, or MRCP may suggest the based on the patient’s age, clinical status, and level of diagnosis, ERCP is usually required for confirmation (34, suspicion for a neoplasm. CT imaging may be adequate to 99, 100). ERCP typically identifies the duct of the pancreatic evaluate patients Ͻ40 yr of age with IARP. ERCP is usually annulus encircling the duodenum (Fig. 6). Pancreas divisum performed, in addition to CT, in patients over 40 yr because is also present in one third of these patients (20). Although of the increased risk of malignancy. EUS is quickly becom- the annular duct may communicate with the ventral duct, it ing a favored procedure because of the ability to diagnose, rarely drains into the dorsal duct, common bile duct, or stage, and biopsy pancreatobiliary tumors (109, 110). In independently into the duodenum (20, 99). EUS may also be fact, most studies have found EUS to have the highest useful in establishing the diagnosis (102). sensitivity for identifying pancreatic neoplasm relative to Gastrojejunostomy (resection of the lesion with anasto- other imaging modalities, especially for tumors Ͻ 2–3cmin mosis of the jejunum and stomach) may be required to diameter (105–108). The diagnosis may be confirmed by bypass the segment of obstructed bowel (98, 101). Pancre- CT-guided biopsy, ERCP-directed brush cytology, or EUS- atic head resection is seldom necessary. Division of the guided fine needle aspiration (110, 111). These procedures annulus, once the procedure of choice, is no longer per- also assist in staging by determining the characteristics of formed because of the inordinate risk of pancreatitis and the primary tumor—namely, tumor size and infiltration into pancreatic fistula formation. major vessels (T stage), regional lymph node involvement 2548 Levy and Geenen AJG – Vol. 96, No. 9, 2001

Figure 7. Pancreatic adenocarcinoma. EUS (linear scanning) demonstrates splenic vein (SV) compression by a pancreatic adenocarcinoma in an elderly patient with pancreatitis.

Figure 8. Intraductal papillary mucinous tumor. The characteristic appearance of a widely patent, fish mouth papilla extruding mucus (N stage), and the presence or absence of distant metastasis in a patient with an intraductal papillary mucinous tumor who (M stage). presented with multiple unexplained episodes of pancreatitis. Im- Most patients with pancreatic cancer present late in their age courtesy of Dr. Maurits J. Wiersema. course and have either locally extensive or metastatic disease (112). The late presentation, aggressive nature, and analyzing aspirated cystic fluid. The fluid viscosity and lack of effective therapies all result in a poor prognosis. amylase level, along with the tumor marker concentration Only 10–20% of patients are considered candidates for (CA 19-9, CA 15-3, CA 72-4, and carcinoembryonic anti- curative resection at the time of diagnosis (113). Accurate gen), may be used to increase the diagnostic yield of cyst staging of pancreatic adenocarcinoma is important to iden- fluid cytology (122, 123). tify the subset of patients who have localized resectable and Ampullary tumors, both benign and malignant, may potentially curable cancers. Although early detection is cru- present with painless jaundice, anemia, or IARP (22, 90, cial to improve prognosis, the determination of resectability 103). Adenomas, which are the most common ampullary is important to help avoid unnecessary surgical intervention. tumors, are premalignant and in general indicate the need Even for patients deemed resectable and undergoing a for surgical resection (124, 125). Ampullary tumors in gen- Whipple procedure (pancreaticoduodenectomy), the 5-yr eral have a more favorable prognosis than pancreatic tumors survival is only about 2% and therefore effective palliation (126, 127), with pancreatoduodenectomy improving the may be the best option for many patients (114). Unresect- prognosis (127, 128). Although this is controversial, benign able or metastatic tumors are effectively palliated by the papillary tumors and localized malignant tumors may be endoscopic placement of a plastic or metal stent across the adequately treated with pylorus-preserving pancreatoduode- site of biliary obstruction. This allows biliary drainage and nectomy or even wide local excision (126, 129, 130). These relief of pruritus, anorexia, and jaundice (115, 116). less invasive surgical techniques offer the advantage of Cystic pancreatic tumors such as serous cystadenomas, reduced morbidity and mortality. mucinous cystadenomas, mucinous cystadenocarcinomas, Various endoscopic techniques are also available for the and intraductal papillary mucinous tumors may also present management of patients with ampullary tumors. An endo- with IARP. Serous cystadenomas are benign, with rare scopic approach is generally reserved for small lesions that exception, and can generally be managed with observation are benign or for carcinoma in situ. Evidence of an invasive alone (117). The other lesions are premalignant or malignant carcinoma and large benign lesions should be managed by and in good operative candidates are generally indications surgical means in patients who are good operative candi- for surgical resection (117–119). Detection is important dates. The ideal endoscopic therapy remains to be identified. even after malignant transformation, because these tumors Tumor excision may be achieved by snare ampullectomy have a better prognosis than ductal adenocarcinoma. Trans- (removal of entire papilla) or piecemeal snare resection abdominal ultrasound, CT, MRI, and EUS are useful in (131, 132). Endoscopic resection is followed by tumor ab- characterizing and differentiating cystic pancreatic tumors lation of residual tissue during the initial endoscopy as well (Fig. 8) (120, 121). The diagnostic yield can be improved by as during surveillance exams. Neodymium:yttrium-alumi- AJG – September, 2001 Idiopathic Acute Recurrent Pancreatitis 2549 num-garnet laser, multipolar cautery, or argon plasma co- agulation may accomplish tumor ablation, with no consen- sus as to the technique of choice (132, 133). Although no studies have confirmed a survival advantage of surveillance after endoscopic resection, this is recommended for ampullary adenomas. This recommendation is based on the adenoma-carcinoma sequence of these lesions, the inability to assure complete ablation, and their expected continued growth. Although some favor surveillance and random biopsy every 3–5 yr (134, 135), we recommend initial follow-up at 3 months and yearly thereafter. Studies comparing endoscopic techniques to surgical intervention for ampullary tumors are small and uncontrolled. We suggest that the tumor histology, extent of the lesion, local expertise, and patient preference must all be considered when selecting the ideal means of therapy.

CHRONIC PANCREATITIS Although patients may clinically present with IARP, many will be found, after ERCP, pancreatic function tests, and EUS, to have already developed some degree of chronic pancreatitis (23, 136). These procedures have a low sensitivity and are unable to diagnose chronic pancreatitis at an early stage. The pancreatic duct is typically normal appear- Figure 9. Chronic calcific pancreatitis. CT demonstrating evidence ing in early chronic pancreatitis, thereby limiting the sensi- of chronic calcific pancreatitis in a patient who had previously been tivity of ERCP. However, pancreatic function testing (e.g., diagnosed with IARP. intraductal secretin test) may help establish the diagnosis at an earlier stage (137). After secretin administration, aliquots chronic pancreatitis may present with IARP as a result of of pancreatic juice are collected via an ERCP cannula po- one of these complications. Transabdominal ultrasound, CT, sitioned in the pancreatic duct. EUS may be the most sen- ERCP, and EUS are used to detect these sequelae and guide sitive study (137, 138), but the findings should be carefully therapy (Fig. 9). interpreted because features of chronic pancreatitis may be seen in the normal population (139). Therefore, the diagno- FURTHER EVALUATION OF IDIOPATHIC ACUTE sis of chronic pancreatitis is best made after considering the RECURRENT PANCREATITIS results of ERCP, pancreatic function tests, and EUS. There are only limited data supporting the use of MRCP for All patients with ARP should undergo an initial evaluation, establishing the diagnosis of chronic pancreatitis. Although which includes a thorough history, routine labs, and imaging it may suggest the diagnosis, MRCP cannot be recom- studies. When this workup fails to reveal an etiology, then mended solely for this purpose at this time (140, 141). a patient can be given the diagnosis of IARP and a more The mortality rate for patients with chronic pancreatitis is extensive evaluation is indicated. three to four times greater than for controls, with mortality Advanced laboratory analysis for patients Ͻ 40 yr of age directly related to pancreatitis in 20% of patients (142, 143). may include an ␣-1-antitrypsin phenotype, CFTR gene anal- The reduction in life span is only 8 yr, with most deaths ysis, a sweat chloride test, trypsin gene studies, and duode- resulting from nonpancreatic causes (142, 143). Therefore, nal aspiration for microcrystals. The level of the tumor though it is important to establish the diagnosis of chronic marker, CA 19-9, should be measured in patients Ͼ 40 yr of pancreatitis, doing so may only minimally impact a patient’s age. The role of genetic testing for hereditary pancreatitis course. Evaluating patients with IARP for chronic pancre- and cystic fibrosis, outside of a research setting, is unclear. atitis not only helps establish the correct diagnosis, but also One can argue a need for testing because of the comfort a determines the prognosis and influences therapy. Patients patient receives in knowing the diagnosis and because of the with chronic pancreatitis may benefit from a trial of pan- potential impact on family planning. Diagnosing hereditary creatic enzyme replacement, a low-fat diet, small meals, pancreatitis may also be important because of the potential insulin for diabetes, and analgesics. influence on pancreatic cancer screening. However, the need Chronic pancreatitis may be complicated by pancreatic for an ideal method of screening these patients are disputed. duct strictures, stones, pseudocyst, fistulas, pseudoaneu- Others may argue that it is currently premature to recom- rysm, or ascites (144–146). Patients with unrecognized mend routine genetic testing because of inadequacies in 2550 Levy and Geenen AJG – Vol. 96, No. 9, 2001 genetic analysis and the absence of established guidelines for genetic counseling. Also, there are no unique endoscopic or surgical approaches for the management of hereditary pancreatitis or cystic fibrosis versus other forms of acute and chronic pancreatitis. Therefore, genetic testing currently has negligible influence on clinical management. We recommend that when genetic testing is not employed, a physician keep a registry of patients suspected of having either disorder, so that they may benefit from newly discovered medications and gene therapy. ERCP reveals a diagnosis in about 70% of patients with IARP after a negative initial evaluation (1, 15). Because the initial episode of pancreatitis may be an isolated event and because of the risk of ERCP, most agree that this procedure is not justified after the first episode of pancreatitis (37, 147). Many believe, however, that ERCP is indicated when the first episode is severe or when a patient has two or more episodes. However, there are some who advocate perform- ing an ERCP after the first episode regardless of the patient’s age or disease severity (37). At the time of the ERCP, bile is aspirated and examined for microcrystals, SOM is performed when SOD is suspected, and the minor papilla is cannulated when pancreas divisum is suspected. EUS is increasingly being used to evaluate patients with IARP because of its sensitivity and safety (148). As compared to transabdominal ultrasound, EUS uses a higher frequency and eliminates the decreased image quality resulting from bowel gas or subcutaneous fat. As a result, EUS offers greater image resolution. EUS has equal or superior sensitivity to other commonly used tests in the diagnosis of Figure 10. Choledocholithiasis. A filling defect (arrow) is identi- microlithiasis and sludge (32, 33). SOD is detected using fied by MRCP, supporting the suspicion of a bile duct stone in a secretin-stimulated EUS (SSEUS) by demonstrating persis- patient with presumed gallstone pancreatitis. tent dilation of the pancreatic duct after secretin administration (149). However, data regarding the utility of SSEUS are limited, and this technique is available in only a few image similar to ERCP. MRCP is helpful for evaluating centers. Therefore, at this point SSEUS must be regarded as acute pancreatitis because it may detect the presence of bile a research tool for studying SOD. EUS has reasonable duct stones (Fig. 10) (64, 150). In patients with IARP, the sensitivity and specificity in detecting structural lesions such primary value of MRCP is to identify anatomical abnormal- as pancreas divisum (63) and an anomalous pancreatobiliary ities such as pancreas divisum, a choledochocele, anoma- junction (96). Occult ampullary and pancreatic tumors may lous pancreatobiliary junction, or annular pancreas (93, 97, also be discovered (109, 110). Finally, EUS can detect the 150, 151). Although MRCP may also detect pancreatico- presence of chronic pancreatitis in patients initially present- biliary tumors (34, 107), chronic pancreatitis (140, 141), and ing with IARP (137–139). microlithiasis (34), its value for diagnosing these disorders Conventional MRI is not generally considered a useful has been minimally studied, and this is not the greatest use tool in the evaluation of patients with IARP except as it of this imaging modality at this time. applies to the diagnosis and staging of pancreatobiliary MRCP offers several advantages over ERCP and is re- neoplasms. Given the limited role and greater utility of other placing diagnostic ERCP in many centers. The advantages imaging modalities, conventional MRI is not routinely rec- include its noninvasiveness, the absence of ERCP-related ommended for the evaluation of patients with IARP. How- complications, avoiding the use of contrast and radiation, ever, experience with MRCP is growing, and its usefulness and its utility in postsurgical patients. However, ERCP in diagnosing disorders associated with IARP is becoming continues to have an important role in the evaluation of increasingly recognized. With the employment of heavily patients with IARP because of the ability to inspect the

T2-weighted sequences, ﬂuid within the bile and pancreatic ampulla, brush and biopsy tissues, aspirate bile ﬂuid, per- ducts is selectively displayed during MRCP, producing an form SOM, and mostly because of its therapeutic potential. AJG – September, 2001 Idiopathic Acute Recurrent Pancreatitis 2551

MANAGEMENT Reprint requests and correspondence: Michael J. Levy, M.D., The Mayo Clinic, Eisenberg 8A, Mayo Clinic, 200 First Street SW, Episodes of acute pancreatitis are treated similarly regard- Rochester, MN 55905. less of the etiology. Intravenous fluids are given, oral intake Received Dec. 12, 2000; accepted June 5, 2001. is withheld, metabolic and electrolyte disturbances are cor- rected, analgesics are administered, and respiratory, renal, and vascular complications are treated as necessary. Specific REFERENCES therapy for given disorders, when available, should be man- 1. Venu RP, Geenen JE, Hogan W, et al. Idiopathic recurrent aged as outlined earlier. pancreatitis: An approach to diagnosis and treatment. Dig Dis Therapeutic options for patients with TIARP are limited, Sci 1989;34:56–60. and little information exists regarding their care. An analysis 2. Steinberg W, Tenner S. Acute pancreatitis. 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