THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.

Vol. 96, No. 9, 2001 ISSN 0002-9270/01/$20.00 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 Acute recurrent pancreatitis (ARP) results most commonly from alcohol abuse or gallstone disease. Initial evaluation fails to detect the cause of ARP in 10 –30% of patients, and as a result the diagnosis of “idiopathic” ARP is given. In these patients, a more extensive evaluation including specialized labs, ERCP, endoscopic ultrasound, or magnetic resonance cholangiopancreatography typically leads to a diagnosis of microlithiasis, sphincter of Oddi dysfunction, or pancreas divisum. Less commonly, hereditary pancreatitis, cystic fibrosis, a choledochocele, annular pancreas, an anomalous pancreatobiliary junction, pancreatobiliary tumors, or chronic pancreatitis are diagnosed. Determining the etiology is important, as it helps to direct therapy, limits further unnecessary evaluation, and may improve a patient’s long term prognosis. (Am J Gastroenterol 2001;96: 2540 –2555. © 2001 by Am. Coll. of Gastroenterology)

INTRODUCTION Acute pancreatitis is an inflammatory process of the pancreas that can affect peripancreatic tissues and distant sites. An etiology can be found in most patients after an attack of acute pancreatitis, with gallstone disease and alcohol abuse most often implicated (Table 1). When patients have more than one clinical episode of acute pancreatitis they are given the diagnosis of acute recurrent pancreatitis (ARP). Most causes of acute pancreatitis can lead to recurrent disease if the underlying factor remains uncorrected (1, 2). The etiology of ARP is found in 70 –90% of patients after an initial evaluation, which includes a thorough history, physical exam, routine labs, and transabdominal ultrasound or CT (Table 2). In the 10 –30% of patients in whom the initial evaluation fails to reveal an etiology, the diagnosis of idiopathic ARP (IARP) is applied (1, 3–5). The extent of the evaluation impacts the frequency with which an etiology can be found, and in turn how often the label idiopathic can be applied. Evaluation and therapy is important because ⬎50% of untreated patients with IARP experience recurrent episodes that may lead to chronic pancreatitis (1, 6).

INITIAL EVALUATION OF ACUTE PANCREATITIS Acute pancreatitis is diagnosed in the proper clinical setting with the aid of laboratory values and imaging studies. Pa-

tients may present with acute epigastric pain, nausea, vomiting, fever, and tachycardia. Laboratory analysis usually reveals elevated pancreatic enzymes and leukocytosis. Abdominal ultrasound and CT help support the diagnosis and exclude other causes. After confirmation of the presence of acute pancreatitis, the focus shifts to determining the etiology. The initial evaluation includes a search for evidence of alcohol abuse, drug-induced pancreatitis, and a family history of pancreatitis, and other clues that may suggest the origin. The serum amylase level is used to help establish the diagnosis of pancreatitis and may be predictive of the underlying pathology. Pancreatitis resulting from gallstones, microlithiasis, or drugs is typically associated with a greater elevation in amylase than lipase (7, 8). The amylase level, as compared to lipase, tends to be lower in alcoholic pancreatitis, hypertriglyceridemia-induced pancreatitis, neoplasia, and chronic pancreatitis (7, 8). Lipase elevation is more specific for pancreatitis than amylase, and the level remains elevated longer, but the level is not predictive of the etiology (9). The ratio of lipase to amylase may help distinguish alcoholic from nonalcoholic pancreatitis, with an increased ratio suggesting alcohol-induced disease (7, 8). Of note, the amylase and lipase levels do not correlate with disease severity and they are not useful for determining prognosis. Liver function tests are routinely measured and may be elevated because of biliary obstruction resulting from gallstones, microlithiasis, a choledochocele, neoplasia of the ampulla or pancreas, or sphincter of Oddi dysfunction (SOD). Liver function tests may also increase as a result of pancreatic head edema, inflammation, or pseudocyst formation. A 3-fold or greater increase in the ALAT level is generally regarded as the best indicator of gallstone-induced pancreatitis (10). One study, however, noted that the best indicator of bile duct stones is a serum total bilirubin ⬎ 1.35 mg/dl on the second day of hospitalization (11). Although it is unclear which laboratory parameter is the most predictive, both may be used to help assess the presence of gallstoneinduced pancreatitis in an individual patient. Metabolic causes of pancreatitis should be excluded by checking the serum calcium and triglyceride levels. These values should be measured soon after admission, or well after resolution of the pancreatitis, because of the drop in calcium and triglyceride levels that can occur during hospitalization (12). Transabdominal ultrasound is a simple, inexpensive, and

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Table 1. Etiologies of Acute Recurrent Pancreatitis

Table 1. (continued)

Alcohol Biliary calculous disease Macrolithiasis (bile duct stone) Microlithiasis (sludge) Biliary cystic disease Choledochal cyst Choledochocele/duplication cyst Congenital anomaly Annular pancreas Anomalous pancreatobiliary junction Pancreas divisum Duodenal obstruction Afferent limb obstructed (Billroth II) Atresia Crohn’s disease Diverticulum Drugs Acetaminophen Azathioprine Didanosine Erythromycin Estrogen Furosemide Histamine-2 receptor antagonists Mercaptopurine Methyldopa Metronidazole Nitrofurantoin Nonsteroidal anti-inflammatory agents Pentamidine Tetracycline Valproic acid Genetic ␣-1-antitrypsin deficiency Cystic fibrosis Hereditary pancreatitis Idiopathic Infection Bacterial Campylobacter jejuni Legionella Leptospirosis Mycobacterium avium complex Mycobacterium tuberculosis Mycoplasma Parasites/worms Ascaris lumbricoides Clonorchis sinensis Cryptosporidium Microsporidium Viral Coxsackievirus Cytomegalovirus Echo virus Epstein-Barr virus Hepatitis (A, B, C) virus HIV Mumps virus Rubella virus Varicella virus Metabolic Hypercalcemia Hyperlipidemia Neoplasm Benign Malignant

Pancreatitis-related complications Fistula/ascites Pseudocyst Stone Stricture Primary sclerosing cholangitis Renal disease Chronic renal failure Dialysis related Sphincter of Oddi dysfunction Toxin Organophosphate insecticides Scorpion bite Tropical Vasculitis Polyarteritis nodosa Systemic lupus erythematosus

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highly sensitive procedure for evaluating the biliary tract (13). CT more accurately delineates the pancreas and may also help identify the cause, assess the severity, and detect complications of pancreatitis (14). Some recommend performing CT only when the first attack is severe, when the course is complicated, or in the elderly. Patients not scanned during the first episode are generally scanned with their second attack regardless of age or disease severity. However, we believe that the yield is great enough to justify a CT in all patients during their first episode. The extent of evaluation required before conferring the diagnosis of IARP varies among studies (3, 15, 16). The purist would demand a complete and exhaustive workup before diagnosis. However, most use this diagnosis when a more limited evaluation, as detailed above, fails to reveal an etiology. A more extensive evaluation may include specialized labs, ERCP, endoscopic ultrasound (EUS), and magnetic resonance cholangiopancreatography (MRCP) (Table 3). This additional workup usually leads to the diagnosis of microlithiasis, SOD, or pancreas divisum (Fig. 1) (1, 2, 4). Other causes such as hereditary pancreatitis (17), cystic fibrosis (18), a choledochocele (19), annular pancreas (20), an anomalous pancreatobiliary junction (21), pancreatobiliary tumors (22), and chronic pancreatitis (23) may be found as well. When this more extensive evaluation fails to reveal an etiology, then the diagnosis of “true” IARP (TIARP) may be assigned. This article will focus on many of the disorders associated with IARP and outline diagnostic and therapeutic options.

MICROLITHIASIS (BILIARY SLUDGE) Although technically different, the terms microlithiasis and biliary sludge are often used interchangeably. Microlithiasis refers to stones of ⬍3 mm in diameter, whereas biliary sludge is a suspension of crystals, mucin, glycoproteins, cellular debris, and proteinaceous material (24). The crystals are composed of calcium bilirubinate, calcium carbonate, or cholesterol monohydrate (5, 25). Microlithiasis is frequently

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Table 2. Initial Evaluation of Acute Recurrent Pancreatitis Parameter History Alcohol abuse Drug intake Family history Laboratory Amylase and lipase (⬎5⫻) (⬍5⫻)

Calcium Liver function tests

Triglycerides Radiographs Ultrasound (transabdominal)

CT

Potential Etiology/Diagnosis

Table 3. Further Evaluation of Idiopathic Acute Recurrent Pancreatitis Parameter

Alcohol Drugs Hereditary Drugs Macrolithiasis (bile duct stone) Microlithiasis (sludge) Alcohol Chronic pancreatitis Hyperlipemia Neoplasm Hypercalcemia Choledochocele Macrolithiasis (bile duct stone) Microlithiasis (sludge) Neoplasm (ampulla, pancreas) Pancreatic head inflammation Pancreatic head pseudocyst Sphincter of Oddi dysfunction Hypertriglyceridemia Chronic pancreatitis Choledochal cyst Choledochocele Macrolithiasis (bile duct stone) Microlithiasis (sludge) Neoplasm (ampulla, pancreas) Annular pancreas Choledochal cyst Choledochocele Chronic pancreatitis Macrolithiasis (bile duct stone) Microlithiasis (sludge) Neoplasm (ampulla, pancreas)

implicated as the cause of IARP. However, some believe that microlithiasis does not cause pancreatitis, but instead indicates the prior presence of larger common bile duct stones that precipitated the pancreatitis. In fact, pancreatitis may induce sludge formation by diminishing gallbladder contractility, thereby leading to some uncertainty regarding the causal relationship between sludge and pancreatitis. Although some studies have detected microlithiasis in as few as 7% of patients with IARP (1), others have found evidence of microlithiasis in approximately two thirds of patients (5, 26). Microlithiasis may lead to pancreatitis through several mechanisms. Small stones may transiently impact the papilla leading to pancreatic duct obstruction and eventual pancreatitis (27). Repeated exposure to microlithiasis may lead to papillary stenosis and SOD, both of which are associated with pancreatitis (28). The optimum method of detecting microlithiasis is yet to be established. Transabdominal ultrasound is a noninvasive study with a sensitivity of about 50% (5, 29). However, repeat examination may improve the yield. Duodenal bile aspiration is an invasive procedure that has a sensitivity of

Laboratory ␣-1-antitrypsin phenotype CFTR gene analysis Sweat electrolytes Trypsin gene studies Tumor marker (CA 19-9) Duodenal aspiration ERCP Appearance (bulging ampulla)

Appearance (duct abnormality)

Bile duct aspiration Brush cytology/biopsy Intraductal secretin test Minor papilla cannulation Sphincter of Oddi manometry Endoscopic ultrasound Appearance/image

Fine needle aspirate Secretin stimulated MRI/MRCP Appearance/image

Potential Etiology/Diagnosis

␣-1-antitrypsin deficiency Cystic fibrosis Cystic fibrosis Hereditary pancreatitis Neoplasm Microlithiasis Choledochocele Duodenal duplication cyst Papillitis Stone (impacted) Tumor Annular pancreas Anomalous pancreatobiliary junction Choledochal cyst Chronic pancreatitis (complications) Macrolithiasis (bile duct stone) Microlithiasis (sludge) Pancreas divisum Microlithiasis Neoplasm Chronic pancreatitis Pancreas divisum Sphincter of Oddi dysfunction

Anomalous pancreatobiliary junction Chronic pancreatitis Macrolithiasis (bile duct stone) Microlithiasis (sludge) Neoplasm (ampullary and pancreatic) Pancreas divisum Neoplasm Sphincter of Oddi dysfunction Annular pancreas Anomalous pancreatobiliary junction Choledochocele Chronic pancreatitis Macrolithiasis (bile duct stone) Microlithiasis (sludge) Neoplasm (ampullary and pancreatic) Pancreas divisum

about 66% (30, 31). ERCP is more invasive, but has a sensitivity of about 85% (25, 29). During ERCP, the common bile duct is directly aspirated for bile. Cholecystokinin is commonly administered before duodenal drainage or ERCP, to enhance gallbladder contractility and improve the yield. In most centers, collected bile is centrifuged at 2000 revolutions/min for 10 min; the sediment is warmed to 37°C

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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.

and then examined by polarized microscopy. The quantity of crystals needed to define a positive result differs among institutions, but most believe that the presence of even a small number of crystals is abnormal. EUS is increasingly being used because it offers the greatest diagnostic sensitivity (Fig. 2) (32, 33). The presence of microlithiasis may also be noted at the time of MRCP (34). Therapy for microlithiasis can significantly reduce the risk of recurrent pancreatitis (5, 26). Several therapeutic options exist for microlithiasis. Laparoscopic cholecystectomy is nearly always curative and generally considered the procedure of choice (5, 26). ERCP with sphincterotomy (incision of the bile duct sphincter) is indicated in high operative risk patients (35, 36). A low-fat diet and ursodeoxycholic acid are acceptable alternatives in high surgical risk patients; however, long term therapy is required (26, 37).

SPHINCTER OF ODDI DYSFUNCTION The sphincter of Oddi is a 5- to 15-mm-long fibromuscular sheath that encircles the terminal common bile duct, pancreatic duct, and common channel. This sphincter regulates the flow of bile and pancreatic juice into the duodenum, inhibits reflux of duodenal contents into the common bile duct and pancreatic duct, and promotes gallbladder filling with bile. SOD is a frequent and treatable cause of IARP and is seen

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 obstruction (dysmotility). This may cause pancreatitis by promoting reflux of bile into the pancreatic duct or by obstructing pancreatic duct outflow (1, 27). Patients with SOD are classified as having either biliary type or pancreatic type disease (Table 4) (40, 41). Subclassifying (types I, II, and III) helps to predict the underlying pathology. Type I disease usually results from stenosis, and type III disease is typically a consequence of dysmotility (40, 41). Subclassifying also helps us to predict the likelihood of pain relief after therapy, with the highest response rate occurring in patients with type I disease. Sphincter of Oddi manometry (SOM) is the gold standard for diagnosing SOD. SOM employs a water-perfused catheter system, which is inserted endoscopically into the common bile duct or pancreatic duct, to measure the sphincter Table 4. Sphincter of Oddi Dysfunction (Geenen & Hogan Classification) Biliary Type

Pancreatic Type

Type I Biliary-type pain LFT elevated CBD dilation Delayed drainage Type II Biliary-type pain One or two of above criteria Type III Biliary-type pain only

Type I Pancreatic-type pain Amylase/lipase elevation PD dilation Delayed drainage Type II Pancreatic-type pain One or two of above criteria Type III Pancreatic-type pain only

CBD ⫽ common bile duct; LFT ⫽ liver function test; PD ⫽ pancreatic duct.

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pressure. The diagnosis is established by finding a hypertensive sphincter of Oddi pressure (⬎40 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 frequent, often severe complications. The use of pancreatic duct stenting for SOD has not been 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 endoscopic sphincterotomy (54). However, because of its lack of long term efficacy and high rate of complications, pancreatic duct stent therapy is not recommended for these patients (55). Endoscopic sphincterotomy is the therapy of choice and is believed to decrease the risk of recurrent pancreatitis (1, 45). Biliary sphincterotomy effectively reduces the pancreatic sphincter pressure (38, 56) and leads to clinical improvement in roughly 80% of patients (39). A lack of improvement is noted when biliary sphincterotomy fails to ablate the pancreatic sphincter (57). In such cases, SOM is repeated to record the pancreatic sphincter pressure and direct further therapy. We favor initially cutting the biliary sphincter and, only if pancreatitis recurs, then later cutting the pancreatic sphincter. Diagnostic and therapeutic interventions are directed toward the biliary sphincter because of the greater risk of pancreatic sphincter manometry and therapy. The complication rate of endoscopic sphincterotomy, when performed for SOD, is greater than for other indications (58). Pancreatitis develops in up to 25% of patients, with 1–3% developing severe pancreatitis. The risk of sphincterotomy is potentially ameliorated by placement of a pancreatic duct stent (59). Surgical sphincteroplasty is an effective alternative (49, 50), but is more invasive and should only be performed when endoscopic sphincterotomy fails. Pancreatic duct stent placement has been less well studied, and most have noted equivocal or disappointing results (47, 48).

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Figure 3. Pancreas divisum. Contrast injection into the major papilla reveals a small ventral pancreatic duct in a patient with pancreas divisum who presented with recurrent episodes of pancreatitis. Image courtesy of Dr. Todd H. Baron.

PANCREAS DIVISUM Pancreas divisum is the most common congenital malformation of the pancreas, effecting 5– 8% of the population (60, 61). Normally, in the sixth to seventh weeks of gestation, the ventral pancreatic bud and bile duct rotate 180° counterclockwise around the foregut and line up caudal to the dorsal pancreatic bud. The ventral and dorsal buds then fuse. As a result, the larger ventral duct (duct of Wirsung) drains the majority of the pancreas through the major papilla. The smaller dorsal duct (duct of Santorini) empties via the smaller accessory (minor) papilla and has little influence on pancreatic drainage. Pancreas divisum results when the embryological ventral and dorsal ducts fail to fuse. As a result, the ventral duct only drains the ventral pancreas. The majority of the pancreas then drains via the dorsal duct through the minor papilla. In these patients, the minor papilla is often stenotic and therefore inhibits the flow of pancreatic juice (15, 61). Although it is controversial, most hold the belief that pancreas divisum is a common cause of IARP and is implicated in about 20% of patients (1, 60). The diagnosis is suspected during ERCP, when injection of contrast media into the major papilla reveals an absent or small ventral pancreatic duct (Fig. 3). The diagnosis is confirmed by minor papilla injection, which usually demonstrates a lack of communication between the dorsal and ventral ducts. However, at times the ventral and dorsal ducts do communicate via a thin filamentous channel (incomplete pancreas divisum). The clinical presentation and response to therapy for “incom-

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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). Endoscopic 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 pancreatic duct stent, which serves as a guide for the sphincterotomy and helps minimize the risk of complications (66). Use of an unflanged stent is important to encourage spontaneous migration (74).

HEREDITARY (FAMILIAL) PANCREATITIS Hereditary pancreatitis is a genetic disorder with an autosomal dominant means of transmission and an estimated 80% penetrance (17). There is no gender predominance, and symptoms typically arise in childhood but may be delayed until the mid-30s (17). This disorder results from a mutation in the cationic trypsinogen gene located on chromosome 7q35 (75). The anomaly involves an arginine to histidine substitution at amino acid 117 (R117H) or asparagine to isoleucine substitution at amino acid 21 (N21I) (76). This mutation leads to formation of an abnormal cationic trypsinogen, impaired inactivation of trypsin, and continuous activation of digestive enzymes (77). It is theorized that pancreatic autodigestion eventually leads to chronic pancreatitis. Patients may present with IARP, but commonly develop chronic pancreatitis with associated abdominal pain, diabetes mellitus, maldigestion, and steatorrhea (17). The lifetime risk of pancreatic cancer is roughly 40% and reportedly 75% with paternal inheritance (78). The diagnosis is easily made in patients developing pancreatitis before 20 yr of age, with affected family members over at least two generations, in the absence of an identifiable cause. However, the diagnosis is sometimes made in patients without these features. ERCP may be normal early on, but in advanced disease typically reveals pancreatic duct dilation, pancreatic duct stones, and pseudocysts (Fig. 4). Therapy does not differ from other causes of acute and chronic pancreatitis, nor does the management of complications. Endoscopic clearance of pancreatic duct stones and surgical pancreatic decompression (pancreaticojejunostomy

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Figure 4. Hereditary pancreatitis. The pancreatogram of a patient with hereditary pancreatitis demonstrating a markedly dilated main pancreatic duct, dilated side branches, and pancreatic duct stones. Image courtesy of Dr. Christopher J. Gostout.

with anastomosis of the pancreatic duct to the jejunum) may be beneficial. However, these therapies cannot be widely recommended because of absence of prospective studies demonstrating their ability to alter the disease course. A conservative approach may be favored, given the tendency for improvement in severity and frequency of attacks over time. However, establishing the diagnosis may be important because of the potential impact on family planning and because of the promise that gene therapy holds. It is important that a patient receives counseling and gives informed consent before genetic testing for hereditary pancreatitis.

CYSTIC FIBROSIS Cystic fibrosis is a genetic disease with an autosomal recessive means of transmission and is the most common disorder affecting the exocrine pancreas (79). It results from a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cyclic adenosine monophosphate–regulated ion channel protein that controls the chloride channel (80). This mutation leads to diminished chloride transport across membranes, dehydrated viscous secretions, and organ dysfunction (81). This defect is linked not only to sinusitis, nasal polyps, chronic bronchitis, and male infertility, but to pancreatitis as well. Most patients with cystic fibrosis develop pancreatic insufficiency and malabsorption due to diminished pancreatic bicarbonate and enzyme secretion (82). Acute recurrent or chronic pancreatitis develops in only 2% of patients, and results from pancreatic duct occlusion by protein-rich acinar secretions, acinar cell damage, and fibrosis (83). Interestingly, patients who develop pancreatitis typically do not

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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). Genetic 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 ⬍10% 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 a short polythymidine tract (5T), versus normal longer thymidine 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, and may be linked to idiopathic pancreatitis (87, 88). Currently, most laboratories are not routinely testing for the 5T allele. Therapy does not differ from that for other causes of acute and chronic pancreatitis. As with hereditary pancreatitis, consideration of the diagnosis is important for family planning and because of the potential future role of gene therapy. Discovery of medications that enhance ductal bicarbonate secretion may one day prevent or slow the progression of pancreatitis.

CHOLEDOCHOCELE Cystic dilation may occur throughout the biliary system and can involve the extrahepatic and/or intrahepatic bile ducts. Todani et al. (89), based on the location, first classified these cysts into five types. A type III cyst, or choledochocele, is a rare congenital or acquired condition in which the intramural segment of the distal pancreatobiliary ductal system is dilated and herniates into the duodenal lumen. They vary in size from a few millimeters to several centimeters. Choledochoceles are associated with biliary and pancreatic disorders, including biliary colic, obstructive jaundice, and IARP (19, 90). Of the five types, only type III cysts have been associated with IARP. Pancreatitis develops when the cyst or its contents (sludge or stones) obstruct pancreatic duct outflow. Although abnormal laboratory values, transabdominal ultrasound, CT, or MRCP may suggest a choledochocele, the

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Figure 5. Choledochocele. Endoscopic appearance of a markedly enlarged major papilla in a patient presenting with several unexplained episodes of acute pancreatitis.

diagnosis is usually confirmed by ERCP (90 –93). Endoscopically, the papilla has a “bulging” appearance and feels soft (pillow sign) when pressure is applied with the catheter tip (Fig. 5) (91). A duodenal duplication cyst, impacted gallstone, papillitis, or tumor can mimic this appearance. The clinical presentation and endoscopic appearance usually make differentiation possible. “Unroofing” the choledochocele by endoscopic sphincterotomy is usually effective (91, 94), with few patients requiring surgical sphincteroplasty (94). Surgery may be preferred for a large choledochocele because of the risk of bleeding with endoscopic therapy (90).

ANOMALOUS PANCREATOBILIARY JUNCTION An anomalous pancreatobiliary junction is defined by an abnormally long (⬎15 mm) common pancreatobiliary channel (92). This anomaly is associated with IARP, choledochal cysts, cholangiocarcinoma, and gallbladder carcinoma (21, 95). The sphincter does not separate the bile and pancreatic ducts, and therefore pancreatic and bile juices may freely flow between ducts and lead to pancreatitis. ERCP and injection of the major papilla reveal the long common channel and simultaneous filling of the bile duct and pancreatic duct. EUS or MRCP may also establish the diagnosis (93, 96, 97). Sphincter ablation by endoscopic sphincterotomy encourages normal flow of bile and pancreatic juice and may decrease the risk of recurrent pancreatitis.

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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 a band of pancreatic tissue partially or completely encircling the duodenum, usually at the level of or just proximal to the major papilla (92). This abnormality is detected in 1/7,000 – 20,000 autopsies (92, 98) and in about 1/1,500 ERCPs (99 –101). The defect occurs in utero when the ventral bud becomes fixed and fails to rotate with the duodenum (92). Symptoms typically begin in childhood and develop as a result of duodenal obstruction, with intractable vomiting most commonly noted (100, 101). Childhood disease is often associated with congenital anomalies such as Down’s syndrome, cardiac defects, tracheoesophageal fistula, Meckel’s diverticulum, and imperforate anus (92, 100). Adults may present with abdominal pain, IARP, chronic pancreatitis, peptic ulcer disease, or biliary obstruction (20, 101). Although barium x-ray, CT, or MRCP may suggest the diagnosis, ERCP is usually required for confirmation (34, 99, 100). ERCP typically identifies the duct of the pancreatic annulus encircling the duodenum (Fig. 6). Pancreas divisum is also present in one third of these patients (20). Although the annular duct may communicate with the ventral duct, it rarely drains into the dorsal duct, common bile duct, or independently into the duodenum (20, 99). EUS may also be useful in establishing the diagnosis (102). Gastrojejunostomy (resection of the lesion with anastomosis of the jejunum and stomach) may be required to bypass the segment of obstructed bowel (98, 101). Pancreatic head resection is seldom necessary. Division of the annulus, once the procedure of choice, is no longer performed because of the inordinate risk of pancreatitis and pancreatic fistula formation.

Five to seven percent of patients with pancreatobiliary tumors, benign or malignant, present with IARP (22, 103, 104). The presence of a neoplasia may be suggested by significant weight loss, steatorrhea, radiological evidence of a solid or cystic pancreatic mass or ductal dilation, and increased age. Although younger patients less commonly have a neoplasia, they are frequently affected by lesions such as islet cell tumors that are often amenable to curative resection. Even the elderly may have potential curable lesions such as cystic neoplasms. Although pancreatic adenocarcinoma is most often implicated, these other tumors must be considered as well. CT, magnetic resonance imaging (MRI), ERCP, and EUS are all useful for identifying pancreatobiliary neoplasms (Fig. 7) (105–108). The extent of the evaluation is typically based on the patient’s age, clinical status, and level of suspicion for a neoplasm. CT imaging may be adequate to evaluate patients ⬍40 yr of age with IARP. ERCP is usually performed, in addition to CT, in patients over 40 yr because of the increased risk of malignancy. EUS is quickly becoming a favored procedure because of the ability to diagnose, stage, and biopsy pancreatobiliary tumors (109, 110). In fact, most studies have found EUS to have the highest sensitivity for identifying pancreatic neoplasm relative to other imaging modalities, especially for tumors ⬍ 2–3 cm in diameter (105–108). The diagnosis may be confirmed by CT-guided biopsy, ERCP-directed brush cytology, or EUSguided fine needle aspiration (110, 111). These procedures also assist in staging by determining the characteristics of the primary tumor—namely, tumor size and infiltration into major vessels (T stage), regional lymph node involvement

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

(N stage), and the presence or absence of distant metastasis (M stage). Most patients with pancreatic cancer present late in their course and have either locally extensive or metastatic disease (112). The late presentation, aggressive nature, and lack of effective therapies all result in a poor prognosis. Only 10 –20% of patients are considered candidates for curative resection at the time of diagnosis (113). Accurate staging of pancreatic adenocarcinoma is important to identify the subset of patients who have localized resectable and potentially curable cancers. Although early detection is crucial to improve prognosis, the determination of resectability is important to help avoid unnecessary surgical intervention. Even for patients deemed resectable and undergoing a Whipple procedure (pancreaticoduodenectomy), the 5-yr survival is only about 2% and therefore effective palliation may be the best option for many patients (114). Unresectable or metastatic tumors are effectively palliated by the endoscopic placement of a plastic or metal stent across the site of biliary obstruction. This allows biliary drainage and relief of pruritus, anorexia, and jaundice (115, 116). Cystic pancreatic tumors such as serous cystadenomas, mucinous cystadenomas, mucinous cystadenocarcinomas, and intraductal papillary mucinous tumors may also present with IARP. Serous cystadenomas are benign, with rare exception, and can generally be managed with observation alone (117). The other lesions are premalignant or malignant and in good operative candidates are generally indications for surgical resection (117–119). Detection is important even after malignant transformation, because these tumors have a better prognosis than ductal adenocarcinoma. Transabdominal ultrasound, CT, MRI, and EUS are useful in characterizing and differentiating cystic pancreatic tumors (Fig. 8) (120, 121). The diagnostic yield can be improved by

Figure 8. Intraductal papillary mucinous tumor. The characteristic appearance of a widely patent, fish mouth papilla extruding mucus in a patient with an intraductal papillary mucinous tumor who presented with multiple unexplained episodes of pancreatitis. Image courtesy of Dr. Maurits J. Wiersema.

analyzing aspirated cystic fluid. The fluid viscosity and amylase level, along with the tumor marker concentration (CA 19-9, CA 15-3, CA 72-4, and carcinoembryonic antigen), may be used to increase the diagnostic yield of cyst fluid cytology (122, 123). Ampullary tumors, both benign and malignant, may present with painless jaundice, anemia, or IARP (22, 90, 103). Adenomas, which are the most common ampullary tumors, are premalignant and in general indicate the need for surgical resection (124, 125). Ampullary tumors in general have a more favorable prognosis than pancreatic tumors (126, 127), with pancreatoduodenectomy improving the prognosis (127, 128). Although this is controversial, benign papillary tumors and localized malignant tumors may be adequately treated with pylorus-preserving pancreatoduodenectomy or even wide local excision (126, 129, 130). These less invasive surgical techniques offer the advantage of reduced morbidity and mortality. Various endoscopic techniques are also available for the management of patients with ampullary tumors. An endoscopic approach is generally reserved for small lesions that are benign or for carcinoma in situ. Evidence of an invasive carcinoma and large benign lesions should be managed by surgical means in patients who are good operative candidates. The ideal endoscopic therapy remains to be identified. Tumor excision may be achieved by snare ampullectomy (removal of entire papilla) or piecemeal snare resection (131, 132). Endoscopic resection is followed by tumor ablation of residual tissue during the initial endoscopy as well as during surveillance exams. Neodymium:yttrium-alumi-

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num-garnet laser, multipolar cautery, or argon plasma coagulation may accomplish tumor ablation, with no consensus 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 appearing in early chronic pancreatitis, thereby limiting the sensitivity of ERCP. However, pancreatic function testing (e.g., intraductal secretin test) may help establish the diagnosis at an earlier stage (137). After secretin administration, aliquots of pancreatic juice are collected via an ERCP cannula positioned in the pancreatic duct. EUS may be the most sensitive study (137, 138), but the findings should be carefully interpreted because features of chronic pancreatitis may be seen in the normal population (139). Therefore, the diagnosis of chronic pancreatitis is best made after considering the results of ERCP, pancreatic function tests, and EUS. There are only limited data supporting the use of MRCP for establishing the diagnosis of chronic pancreatitis. Although it may suggest the diagnosis, MRCP cannot be recommended solely for this purpose at this time (140, 141). The mortality rate for patients with chronic pancreatitis is three to four times greater than for controls, with mortality directly related to pancreatitis in 20% of patients (142, 143). The reduction in life span is only 8 yr, with most deaths resulting from nonpancreatic causes (142, 143). Therefore, though it is important to establish the diagnosis of chronic pancreatitis, doing so may only minimally impact a patient’s course. Evaluating patients with IARP for chronic pancreatitis not only helps establish the correct diagnosis, but also determines the prognosis and influences therapy. Patients with chronic pancreatitis may benefit from a trial of pancreatic enzyme replacement, a low-fat diet, small meals, insulin for diabetes, and analgesics. Chronic pancreatitis may be complicated by pancreatic duct strictures, stones, pseudocyst, fistulas, pseudoaneurysm, or ascites (144 –146). Patients with unrecognized

Figure 9. Chronic calcific pancreatitis. CT demonstrating evidence of chronic calcific pancreatitis in a patient who had previously been diagnosed with IARP.

chronic pancreatitis may present with IARP as a result of one of these complications. Transabdominal ultrasound, CT, ERCP, and EUS are used to detect these sequelae and guide therapy (Fig. 9).

FURTHER EVALUATION OF IDIOPATHIC ACUTE RECURRENT PANCREATITIS All patients with ARP should undergo an initial evaluation, which includes a thorough history, routine labs, and imaging studies. When this workup fails to reveal an etiology, then a patient can be given the diagnosis of IARP and a more extensive evaluation is indicated. Advanced laboratory analysis for patients ⬍ 40 yr of age may include an ␣-1-antitrypsin phenotype, CFTR gene analysis, a sweat chloride test, trypsin gene studies, and duodenal aspiration for microcrystals. The level of the tumor marker, CA 19-9, should be measured in patients ⬎ 40 yr of age. The role of genetic testing for hereditary pancreatitis and cystic fibrosis, outside of a research setting, is unclear. One can argue a need for testing because of the comfort a patient receives in knowing the diagnosis and because of the potential impact on family planning. Diagnosing hereditary pancreatitis may also be important because of the potential influence on pancreatic cancer screening. However, the need for an ideal method of screening these patients are disputed. Others may argue that it is currently premature to recommend routine genetic testing because of inadequacies in

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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 performing 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 microlithiasis and sludge (32, 33). SOD is detected using secretin-stimulated EUS (SSEUS) by demonstrating persistent 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 centers. Therefore, at this point SSEUS must be regarded as a research tool for studying SOD. EUS has reasonable sensitivity and specificity in detecting structural lesions such as pancreas divisum (63) and an anomalous pancreatobiliary junction (96). Occult ampullary and pancreatic tumors may also be discovered (109, 110). Finally, EUS can detect the presence of chronic pancreatitis in patients initially presenting with IARP (137–139). Conventional MRI is not generally considered a useful tool in the evaluation of patients with IARP except as it applies to the diagnosis and staging of pancreatobiliary neoplasms. Given the limited role and greater utility of other imaging modalities, conventional MRI is not routinely recommended for the evaluation of patients with IARP. However, experience with MRCP is growing, and its usefulness in diagnosing disorders associated with IARP is becoming increasingly recognized. With the employment of heavily T2-weighted sequences, fluid within the bile and pancreatic ducts is selectively displayed during MRCP, producing an

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Figure 10. Choledocholithiasis. A filling defect (arrow) is identified by MRCP, supporting the suspicion of a bile duct stone in a patient with presumed gallstone pancreatitis.

image similar to ERCP. MRCP is helpful for evaluating acute pancreatitis because it may detect the presence of bile duct stones (Fig. 10) (64, 150). In patients with IARP, the primary value of MRCP is to identify anatomical abnormalities such as pancreas divisum, a choledochocele, anomalous pancreatobiliary junction, or annular pancreas (93, 97, 150, 151). Although MRCP may also detect pancreaticobiliary tumors (34, 107), chronic pancreatitis (140, 141), and microlithiasis (34), its value for diagnosing these disorders has been minimally studied, and this is not the greatest use of this imaging modality at this time. MRCP offers several advantages over ERCP and is replacing diagnostic ERCP in many centers. The advantages include its noninvasiveness, the absence of ERCP-related complications, avoiding the use of contrast and radiation, and its utility in postsurgical patients. However, ERCP continues to have an important role in the evaluation of patients with IARP because of the ability to inspect the ampulla, brush and biopsy tissues, aspirate bile fluid, perform SOM, and mostly because of its therapeutic potential.

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MANAGEMENT Episodes of acute pancreatitis are treated similarly regardless of the etiology. Intravenous fluids are given, oral intake is withheld, metabolic and electrolyte disturbances are corrected, analgesics are administered, and respiratory, renal, and vascular complications are treated as necessary. Specific therapy for given disorders, when available, should be managed as outlined earlier. Therapeutic options for patients with TIARP are limited, and little information exists regarding their care. An analysis of the data from available studies is complicated given the differences in patient population, therapy administered, and outcomes measured. Most studies included patients with identifiable disorders such as SOD or pancreas divisum along with TIARP. In these studies the results were usually combined, making it difficult to extrapolate the data for patients with TIARP. Many trials only performed a limited evaluation, thereby increasing the likelihood of missing an existing disorder. Most studies have also been noncontrolled and nonrandomized. A number of “nonvalidated” therapies therefore exist for TIARP. Smooth muscle relaxers such as calcium channel blockers or nitrates may abort an attack if taken at the onset of symptoms. Pancreatic enzymes inhibit pancreatic enzyme secretion and may be helpful, especially for those patients with idiopathic chronic pancreatitis (152). There is literature to suggest that antioxidants such as ␤-carotene, methionine, vitamin C, and vitamin E may be beneficial by inhibiting the release of oxygen-derived free radicals (153). Several centers have reported favorable results with the use of pancreatic duct stents or endoscopic sphincterotomy (biliary or pancreatic) in patients with TIARP (47, 154). There is only one prospective, randomized trial evaluating the use of pancreatic duct stents for this indication (155). Patients randomized to stent placement suffered fewer episodes of pancreatitis during the nearly 3-yr follow-up. However, such therapy cannot be widely supported outside of a research protocol until more data are available. Because of the prevalence of microlithiasis in patients with IARP and because of the high false negative rate of bile acid analysis, it may be reasonable to proceed with empiric laparoscopic cholecystectomy (15, 156, 157). Empiric administration of ursodeoxycholic acid and a low-fat diet are a reasonable alternative in high surgical risk patients. In conclusion, ARP may be caused by a number of disorders. Often, our greatest challenge is to establish the correct diagnosis in those patients without a history of gallstone disease or alcohol abuse. In the 10 –30% of patients with “idiopathic” acute recurrent pancreatitis, the use of specialized laboratory analysis, ERCP, EUS, and MRCP may lead to the diagnosis. These procedures may be used not only to establish the correct diagnosis, but also to direct therapy and often improve a patient’s long term prognosis.

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Reprint requests and correspondence: Michael J. Levy, M.D., The Mayo Clinic, Eisenberg 8A, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Received Dec. 12, 2000; accepted June 5, 2001.

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