Causes of recurrent acute pancreatitis are summarized in Table 1 .
Microlithiasis and Biliary Sludge
Although the terms are used interchangeably, microlithiasis specifically refers to cholesterol monohydrate, calcium bilirubinate, or calcium carbonate stones measuring < 2 mm, whereas sludge is a suspension of crystals, mucin, glycoproteins, and cellular debris. In most reports, bile aspiration from the duodenum or from the bile duct yields microlithiasis in 50% to 73% of patients with RAP with the gallbladder in situ.[5,6,7,8] Others have found microlithiasis in only 7% of patients with IRAP. Microlithiasis is less often implicated as a cause of RAP in patients who have undergone cholecystectomy.[9,10]
The need for crystal analysis is controversial given the high incidence of microlithiasis in patients with RAP and an intact gallbladder. The yield of bile aspiration varies by collection site -- lower for the duodenum, higher for gallbladder specimens. Cholecystokinin is often administered to promote gallbladder contractility and increase the diagnostic yield. The sample must be processed immediately for adequate interpretation, and a negative aspirate does not rule out microlithiasis. Microlithiasis and sludge may also be evaluated by EUS, which can help rule out other causes of RAP, such as chronic pancreatitis, cysts, or tumors. EUS has limited availability and the results are highly operator-dependent. Transabdominal ultrasound is a noninvasive alternative, but has a sensitivity of only about 50%.[8,9,12] However, repeat examination may improve the yield.
Microlithiasis may lead to pancreatitis through several mechanisms. Small stones may transiently impact the papilla, leading to pancreatic duct obstruction and eventual pancreatitis. Repeated exposure to microlithiasis may lead to papillary stenosis and SOD, both of which are associated with pancreatitis. As with stones, sludge may cause obstruction. While often transient, sludge may recur, depending on the inciting factor (eg, total parenteral nutrition, pregnancy) and lead to subsequent stone formation in 12.5% of patients.[8,15] Some investigators believe that microlithiasis does not cause pancreatitis, but instead indicates the past presence of larger common bile duct stones that precipitated the pancreatitis. Pancreatitis may induce sludge formation by diminishing gallbladder contractility, thereby leading to some uncertainty regarding the causal relationship between sludge and pancreatitis.
Pancreatitis recurrence rates decrease following cholecystectomy or ursodeoxycholic acid therapy.[7,9,11] Laparoscopic cholecystectomy is favored for good operative candidates, with endoscopic sphincterotomy and/or ursodeoxycholic acid being suitable alternatives for poor operative candidates and/or the elderly.[4,7]
Sphincter of Oddi Dysfunction
SOD is reported to cause one third of all cases of IRAP[3,10,16,17] from diminished transsphincteric flow of bile or pancreatic juice due to organic obstruction (stenosis) or functional obstruction (dysmotility). Pancreatitis may result from bile reflux into the pancreatic duct or from pancreatic duct outflow obstruction.[3,13] SOD is classified based on clinical, radiologic, and laboratory findings.[18,19] Classifying patients helps predict the etiology and likelihood of pain relief following therapy ( Table 2 ).
Sphincter of Oddi manometry (SOM) is the diagnostic gold standard and uses a water-perfused catheter system that is inserted into the common bile duct or pancreatic duct. The diagnosis is established by finding a hypertensive sphincter of Oddi pressure (> 40 mmHg). However, SOM is a nonstandardized test, with normal manometric values based on small control groups. In addition, pancreatitis develops in up to 33% of patients, with 1% to 3% developing severe pancreatitis.[3,16,17] As a result, SOM should be reserved for patients with clinically significant or disabling symptoms in whom sphincter ablation is planned when confirming the diagnosis. This procedure is unnecessary, and empiric therapy is reasonable in type 1 disease due to the prevalence of SOD and the likelihood of response in this subset. Although the role of SOM/endoscopic sphincterotomy in patients with type 2 or 3 SOD is less clear, it is our approach to perform SOM in this setting. The utility of empiric therapy vs SOM is under investigation for patients with type 2 disease because of the relative risk of SOM compared with empiric sphincterotomy. SOD may also be evaluated by indirect methods aimed at detecting a delay in pancreatic juice drainage. Evidence of delayed drainage may be noted following contrast injection during ERCP, or with persistent dilatation of the pancreatic duct after secretin stimulation on imaging studies such as EUS, transabdominal ultrasound, and magnetic resonance imaging (MRI).
Noninvasive therapies, such as a low-fat diet, analgesics, anticholinergics, calcium-channel blockers, and nitrates, are seldom effective.[23,24] Endoscopic sphincterotomy is the therapy of choice and is believed to decrease the risk of recurrent pancreatitis.[3,25] Biliary sphincterotomy, possibly by ablation of a common channel, may also reduce the pancreatic sphincter pressure,[19,26,27] leading to a clinical improvement in about 80% of patients. A lack of improvement may be due to failure of the biliary sphincterotomy to ablate the pancreatic sphincter. There is no clear evidence to support the practice of performing dual manometry and possible sphincterotomy. In type 1 and type 2 SOD it appears logical to approach the sphincter that correlates with the clinical presentation. In patients with presumed pancreatic SOD after undergoing biliary sphincterotomy, SOM is repeated to direct further therapy. Due to the greater risk of pancreatitis following pancreatic vs biliary sphincterotomy, we favor initially cutting the biliary sphincter, and only if pancreatitis recurs is the pancreatic sphincter evaluated. The risk of sphincterotomy is ameliorated by placement of a pancreatic duct stent. Some clinicians question the existence of SOD as a disease entity and any causal relation to pancreatitis. A better understanding of the pathophysiology of RAP through the discovery of genetic abnormalities will hopefully resolve this issue and will likely decrease the frequency with which pancreatitis is attributed to SOD.
Pancreas divisum is the most common pancreatic congenital malformation; it leads to pancreatic drainage primarily through the minor papilla via the dorsal duct of Santorini, as opposed to the more common route, through the major papilla via the ventral duct of Wirsung. The minor papilla may be stenotic and inhibit the flow of pancreatic juice, thus leading to pancreatitis.[32,33,34] Although up to 26% of patients with RAP may have pancreas divisum, this anatomic variant is present in 5% to 8% of the general population.[33,35] Therefore, the role of pancreas divisum in RAP is debated. This suspicion is supported by the recent finding that the prevalence of CFTR mutations was similar in patients with pancreas divisum with recurrent acute pancreatitis and true idiopathic recurrent acute pancreatitis, whereas the prevalence of CFTR mutations in patients with pancreas divisum but without recurrent acute pancreatitis was similar to controls without pancreatitis. The diagnosis is suspected during ERCP, when injection of contrast media into the major papilla reveals an absent or small ventral pancreatic duct, and is confirmed by minor papilla injection demonstrating a lack of communication between the dorsal and ventral ducts. Pancreas divisum should be confirmed, otherwise pseudodivisum caused by tumor could be missed.
Endoscopic[37,38] therapies are designed to relieve minor papilla outflow obstruction, and they decrease the rate of recurrent pancreatitis in 70% to 90% of patients followed up to 5 years. Patients with a dilated pancreatic duct may be most likely to benefit from therapy. Catheter dilatation and stenting are discouraged because of the lack of efficacy[38,40,41] and the risk of chronic pancreatitis following prolonged stenting.[42,43] Minor papilla sphincterotomy is the therapy of choice, with combined use of short-term stents to minimize the risk of pancreatitis.[37)] Unflanged stents are used to facilitate spontaneous migration.
Anatomic variations or malformations other than pancreas divisum may lead to RAP, and these include periampullary diverticula, duodenal duplication cysts, choledochocele, anomalous pancreatobiliary junction, and annular pancreas. The relationship to RAP is limited to case series. One would expect a higher representation of these abnormalities in RAP even when considering their infrequent occurrence. This suggests that the majority of patients with these abnormalities do not develop RAP, and other, more common causes should be ruled out before attributing pancreatitis to anatomic abnormalities. Recurrent pancreatitis may be the presentation in up to 14% of patients with pancreaticobiliary tumors.[45,46] Actually, ampullary adenocarcinoma has been discovered by biopsy in patients suspected of having SOD. Thus, a level of suspicion is necessary to not miss this diagnosis. Pancreas cysts, especially intrapapillary mucinous neoplasm, may cause recurrent pancreatitis.
Medication and Metabolic Causes
Drugs cause acute pancreatitis due to either a hypersensitivity reaction or direct toxic effect. A careful history, including use of over-the-counter and homeopathic medications, should be obtained. Hypertriglyceridemia, with levels usually > 1000 mg/dL, may be associated with RAP; however, elevation may be a phenomenon of acute pancreatitis itself, and a fasting lipid panel therefore should be obtained after an acute episode to try to establish causality. Hypercalcemia is another cause that should be evaluated after an acute episode, because levels may be low during an attack.[1,31]
Genetic mutations are increasingly recognized to predispose to RAP; chronic pancreatitis or pancreatic cancer may eventually ensue. Hereditary pancreatitis has an autosomal dominant mechanism of transmission, with approximately 80% penetrance, usually resulting from a mutation (R122H or N29I) in the cationic trypsinogen gene located on chromosome 7q35. The latter can lead to impaired trypsin inactivation, continuous activation of digestive enzymes, IRAP, chronic pancreatitis, and pancreatic cancer in about 40% of cases.[49,50] Most patients develop RAP or have evidence of chronic pancreatitis at a young age (< 20 years of age), and have affected family members over 2 generations. Endoscopic clearance of pancreatic duct stones and surgical pancreatic decompression should be cautiously performed, because they do not clearly alter the disease course. A conservative approach may be favored given the tendency for improvement in severity and frequency of attacks over time.
Cystic fibrosis has an autosomal recessive means of transmission. This disorder results from a mutation in the CFTR (cystic fibrosis transmembrane regulator) gene encoding a cAMP-regulated chloride ion channel protein. Although over 900 mutations have been identified -- the delta F508 mutation (a 3-base pair deletion that results in the absence of phenylalanine at amino acid position 508) is the most common, present in 70% of cases. The clinical relevance of other mutations is uncertain. It is easier to comprehend an association between homozygous mutations and RAP, but compound heterozygous mutations have also been found in patients with RAP, suggesting a role in the disease as well. This defect is linked to sinusitis, nasal polyps, chronic bronchitis, male infertility, and pancreatitis. Most patients with cystic fibrosis develop pancreatic insufficiency and malabsorption. Recurrent acute or chronic pancreatitis develops in only 2% of patients. It is interesting to note that patients who develop pancreatitis typically do not suffer from pancreatic insufficiency and do not manifest most of the phenotypic abnormalities. The significance of these mutations is becoming more evident with the recent finding that the presence of CFTR mutations and not of pancreas divisum appeared to be the significant risk factor for RAP.
Mutations in the pancreatic secretory trypsin inhibitor (serum protease inhibitor Kazal type 1 or SPINK-1) are considered disease modifiers mostly in the presence of CFTR or cationic trypsinogen gene mutations rather than a cause of RAP or chronic pancreatitis, except for tropical pancreatitis, where the mutation is present in a significant number of patients.[52,53] Recommendations for genetic testing in pancreatitis have been published.
Although patients may clinically present with IRAP, many will be found -- after performing ERCP, pancreatic function tests, and EUS -- to have already developed chronic pancreatitis.[49,55,56] These procedures have a low sensitivity for diagnosing early chronic pancreatitis. The pancreatic duct is typically normal in early chronic pancreatitis, thereby limiting the sensitivity of ERCP. Pancreatic function tests may help establish the diagnosis at an earlier stage. EUS may be the most sensitive study, but the findings should be carefully interpreted because features of chronic pancreatitis may be seen in the normal population. The diagnosis is best made after considering the results of ERCP, pancreatic function text, and EUS. While it may suggest the diagnosis, MRCP cannot be recommended solely for this purpose at this time. Management implications include enrollment in pain control programs without the stigma of "chronic abdominal pain" and avoidance of potentially morbid interventions.
Autoimmune pancreatitis is a form of chronic pancreatitis that may be associated with other autoimmune diseases, such as Sjögren's syndrome, thyroiditis, and others, or it may occur solitarily. This entity is difficult to differentiate from pancreatic adenocarcinoma because it usually presents in older males with painless biliary obstruction. This is the only form of chronic pancreatitis responsive to treatment because it may improve with steroids.
Five percent to 14% of patients with pancreatobiliary tumors present with IRAP, which may be suggested by weight loss, steatorrhea, new onset (< 3 years) diabetes mellitus, radiologic evidence of a mass or ductal dilatation, and increased age.[45,46,62] Pancreatic cysts, especially intrapapillary mucinous neoplasm, may present with acute pancreatitis and should be ruled out. Computed tomography (CT), MRI, ERCP, and EUS are all useful modalities for identifying pancreatobiliary neoplasms.[63,64,65,66] EUS is quickly becoming favored due to the ability to diagnose, stage, and biopsy.[67,68] EUS has the highest sensitivity for identifying pancreatic neoplasia, especially tumors < 2-3 cm in diameter.[63,64] The diagnosis may be confirmed by CT-guided biopsy, ERCP-directed brush cytology, or EUS fine-needle aspiration.[68,69] While supporting data are lacking, further evaluation with a dedicated pancreas protocol CT scan or EUS after the inflammation has subsided is reasonable and recommended. This is especially true in patients at higher risk of having neoplasia, such as patients with new-onset diabetes mellitus, weight loss, a family history of pancreatic neoplasia, chronic pancreatitis, or those older than 50 years of age.
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