“Idiopathic” pancreatitis
2005; Elsevier BV; Volume: 128; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2005.01.037
ISSN1528-0012
AutoresPeter V. Draganov, Chris E. Forsmark,
Tópico(s)Pancreatic and Hepatic Oncology Research
ResumoA 38-year-old previously healthy man is seen in the emergency room with constant epigastric pain radiating to the back, associated with nausea and vomiting. Pancreatitis is suspected due to marked elevations in lipase and amylase. The patient takes no medications and has no family history of pancreatitis. He has no history of trauma. His calcium, triglyceride, and liver chemistries are normal. Right upper quadrant ultrasound is normal. An abdominal CT scan shows mild enlargement of the pancreas with stranding into the peripancreatic fat. The patient is admitted with a diagnosis of acute "idiopathic" pancreatitis. There are an extensive number of potential etiologies for acute pancreatitis (AP) (Table 1). Determining the etiology of AP is of crucial importance for several reasons. First, if the underlying cause of pancreatitis is not treated the patient's condition may deteriorate (eg, ongoing bile duct obstruction during attack of biliary pancreatitis). Second, recurrent attacks of pancreatitis may occur if the underlying condition is not corrected and in some cases they will be severe or might lead to the development of chronic pancreatitis.1Seidensticker F. Otto J. Lankisch P.G. Recovery of the pancreas after acute pancreatitis is not necessarily complete.Int J Pancreatol. 1995; 17: 225-229PubMed Google Scholar Third, a serious underlying disease requiring specific therapy (eg, pancreatic cancer) may be the precipitating factor for AP.Table 1Etiologies of Acute PancreatitisAlcoholIdiopathicAutoimmune pancreatitisInfectionBiliary calculous disease Bacterial Macrolithiasis (bile duct stone) Campylobacter jejuni Microlithiasis (biliary crystals) LegionellaBiliary cystic disease Leptospirosis Choledochal cyst Mycobacterium avium complex Choledochocele/duplication cyst Mycobacterium tuberculosisCongenital anomaly Mycoplasma Annular pancreas Parasites/worms Anomalous pancreato-biliary junction Ascaris lumbricoides Pancreas divisum Clonorchis sinensisChronic pancreatitis CryptosporidiumDuodenal obstruction Microsporidia Afferent limb obstructed (Billroth II) Viral Atresia Coxsackievirus Crohn's disease Cytomegalovirus Diverticulum Echo virusDrugs Epstein-Barr virus Acetaminophen Hepatitis (A, B, C) virus Azathioprine HIV Didanosine Mumps virus Erythromycin Rubella virus Estrogen Varicella virus FurosemideMetabolic Histamine-2 receptor antagonists Hypercalcemia Mercaptopurine Hyperlipidemia Methyldopa Benign Metronidazole Malignant NitrofurantoinRenal disease Nonsteroidal anti-inflammatory agents Chronic renal failure Pentamidine Dialysis related TetracyclineSphincter of Oddi dysfunction Valproic acidToxinGenetic Organophosphate insecticides Alfa 1-antitrypsin deficiency Scorpion bite Cystic fibrosisTrauma Hereditary pancreatitisTropicalIatrogenicVasculitis ERCP Polyarteritis nodosa Abdominal surgery Systemic lupus erythematosus Open table in a new tab The cause for AP is easily identified in 70% to 90% of patients after an initial evaluation consisting of history, physical examination, focused laboratory testing, and routine radiologic evaluation (Table 2).Table 2Initial Evaluation of Acute PancreatitisParameterPotential Etiology/DiagnosisHistory and Physical examination Alcohol abuseAlcohol Drug intakeDrugs Family historyHereditary JaundiceMacrolithiasis (bile duct stone)Microlithiasis (biliary crystals)Neoplasm (ampulla, pancreas)Sphincter of Oddi dysfunction Eruptive or tuberous xanthomasHypertriglyceridemiaLaboratory evaluation Amylase and lipase elevated > 5 × upper limit of normalDrugsMacrolithiasis (bile duct stone)Microlithiasis (biliary crystals) Amylase and lipase elevated >5 × upper limit of normalAlcoholChronic pancreatitisHyperlipemiaNeoplasm CalciumHypercalcemia Liver function testsCholedochoceleMacrolithiasis (bile duct stone)Microlithiasis (biliary crystals)Neoplasm (ampulla, pancreas)Pancreatic head inflammationPancreatic head pseudocystSphincter of Oddi dysfunction TriglyceridesHypertriglyceridemiaRadiological evaluation Ultrasound (transabdominal)Chronic pancreatitisCholedochal cystCholedochoceleMacrolithiasis (bile duct stone)Microlithiasis (biliary crystals)Neoplasm (ampulla, pancreas) CTAnnular pancreasCholedochal cystCholedochoceleChronic pancreatitisMacrolithiasis (bile duct stone)Neoplasm (ampulla, pancreas) Open table in a new tab The search for the etiology of an attack of AP begins with a careful history and physical examination. A history of alcohol abuse, medication use, gallstone disease, vasculitis, abdominal trauma, elevated triglycerides, recent endoscopic retrograde cholangiopancreatography (ERCP), prior abdominal surgery, inflammatory bowel disease, or family history of pancreatitis can give clues as to the origin of AP. Physical examination may also rarely provide a clue as to the etiology of AP. The presence of jaundice suggests gallstones, pancreatic or ampullary neoplasm, choledochal cyst, or sphincter of Oddi dysfunction (SOD). Eruptive xanthomas on the extensor surfaces of the extremities and the buttocks or tuberous xanthomas found over the large joints of the hand suggest hypertriglyceridemia as the cause. The serum amylase and lipase levels are used to help establish the diagnosis of AP but also may provide some insight into the underlying etiology. Pancreatitis resulting from gallstones, microlithiasis, or drugs is typically associated with the highest levels of amylase and lipase and the degree of elevation of amylase tends to be greater than lipase.2Gumaste V.V. Dave P.B. Weissman D. Messer J. Lipase/amylase ratio. A new index that distinguishes acute episodes of alcoholic from nonalcoholic acute pancreatitis.Gastroenterology. 1991; 101: 1361-1366PubMed Google Scholar, 3Tenner S.M. Steinberg W. The admission serum lipase:amylase ratio differentiates alcoholic from nonalcoholic acute pancreatitis.Am J Gastroenterol. 1992; 87: 1755-1758PubMed Google Scholar Amylase and lipase levels are usually somewhat lower and equally abnormal when alcohol, hypertriglyceridemia, cancer, or chronic pancreatitis is the underlying cause.2Gumaste V.V. Dave P.B. Weissman D. Messer J. Lipase/amylase ratio. A new index that distinguishes acute episodes of alcoholic from nonalcoholic acute pancreatitis.Gastroenterology. 1991; 101: 1361-1366PubMed Google Scholar, 3Tenner S.M. Steinberg W. The admission serum lipase:amylase ratio differentiates alcoholic from nonalcoholic acute pancreatitis.Am J Gastroenterol. 1992; 87: 1755-1758PubMed Google Scholar Elevations of liver chemistries are seen most commonly in patients with AP due to gallstones, pancreatic or ampullary neoplasm, microlithiasis, choledochal cyst, choledochocele, and SOD. A number of studies have attempted to analyze the predictive ability of liver chemistries to identify patients with gallstone pancreatitis. An elevation of the ALT of greater than or equal to 150 IU/L (approximately a 3-fold elevation) is associated with a 95% probability of gallstone pancreatitis.4Tenner S. Dubner H. Steinberg W. Predicting gallstone pancreatitis with laboratory parameters A meta-analysis.Am J Gastroenterol. 1994; 89: 1863-1866PubMed Google Scholar Similarly, a bilirubin level greater than 2.0 mg/dL is associated with gallstone pancreatitis.5Neoptolemos J.P. London N. Bailey I. Shaw D. Carr-Locke D.L. Fossard D.P. Moossa A.R. The role of clinical and biochemical criteria and endoscopic retrograde cholangiopancreatography in the urgent diagnosis of common bile duct stones in acute pancreatitis.Surgery. 1986; 100: 732-742PubMed Google Scholar Although elevated serum calcium or triglycerides may be the cause of AP, during hospitalization these levels may decrease to normal due to fasting (triglycerides) or administration of intravenous fluids (calcium). Therefore, levels should be measured at the time of admission, or if that is not possible, after resolution of the pancreatitis. Transabdominal ultrasound (US) and computed tomography (CT) are the two imaging modalities most frequently used in patients with AP. These techniques tend to be complementary. US is very good at detecting gallbladder stones (accuracy of > 90%). The sensitivity of US for the detection of dilated bile ducts ranges in various studies from 55% to 91%.6Pedersen O.M. Nordgard K. Kvinnsland S. Value of sonography in obstructive jaundice. Limitations of bile duct caliber as an index of obstruction.Scand J Gastroenterol. 1987; 22: 975-981Crossref PubMed Scopus (33) Google Scholar, 7Pasanen P.A. Partanen K.P. Pikkarainen P.H. Alhava E.M. Janatuinen E.K. Pirinen A.E. A comparison of ultrasound, computed tomography and endoscopic retrograde cholangiopancreatography in the differential diagnosis of benign and malignant jaundice and cholestasis.Eur J Surg. 1993; 159: 23-29PubMed Google Scholar, 8Lapis J.L. Orlando R.C. Mittelstaedt C.A. Staab E.V. Ultrasonography in the diagnosis of obstructive jaundice.Ann Intern Med. 1978; 89: 61-63Crossref PubMed Scopus (34) Google Scholar, 9Salem S. Vas W. Ultrasonography in evaluation of the jaundiced patient.J Can Assoc Radiol. 1981; 32: 30-34PubMed Google Scholar The reported sensitivity of US for the detection of common bile duct (CBD) stones is limited and ranges from 20% to 75%. Visualization of the pancreas with US in the face of ongoing AP tends to be poor due to overlying intestinal gas.10Agarwal N. Pitchumoni C.S. Sivaprasad A.V. Evaluating tests for acute pancreatitis.Am J Gastroenterol. 1990; 85: 356-366PubMed Google Scholar From that perspective, US is most useful when biliary pancreatitis is suspected, and in a similar vein to evaluate for gallstones in patients with no obvious cause for AP. Contrast enhanced CT more accurately delineates the pancreas but less accurately identifies gallstones. Abdominal CT is of particular use to confirm the diagnosis of AP if it is in question, to stage the severity of AP (by detecting the presence of local complications such as acute fluid collections, pancreatic abscess, pseudocyst, and pancreatic necrosis) and when the etiology of the pancreatic attack is unclear. It is important to obtain an intravenous contrast-enhanced CT. A noncontrast CT will be of very limited value since it will not detect pancreatic necrosis and pancreatic neoplasm can easily be missed. There has been a concern that the use of intravenous contrast media early in the course of AP might increase or precipitate pancreatic necrosis. Decreased pancreatic capillary flow rates after intravenous contrast administration have been observed in two animal studies.11Schmidt J. Hotz H.G. Foitzik T. Ryschich E. Buhr H.J. Warshaw A.L. Herfarth C. Klar E. Intravenous contrast medium aggravates the impairment of pancreatic microcirculation in necrotizing pancreatitis in the rat.Ann Surg. 1995; 221: 257-264Crossref PubMed Scopus (91) Google Scholar, 12Foitzik T. Lewandrowski K.B. Fernandez-del Castillo C. Rattner D.W. Klar E. Warshaw A.L. Exocrine hyperstimulation but not pancreatic duct obstruction increases the susceptibility to alcohol-related pancreatic injury.Arch Surg. 1994; 129: 1081-1085Crossref PubMed Scopus (31) Google Scholar One retrospective study found that patients who underwent contrast-enhanced CT had longer hospitalization than those who did not.13McMenamin D.A. Gates Jr, L.K. A retrospective analysis of the effect of contrast-enhanced CT on the outcome of acute pancreatitis.Am J Gastroenterol. 1996; 91: 1384-1387PubMed Google Scholar In a cohort analytic study an increased incidence of local and systemic complications was observed in patients with mild AP who underwent contrast enhanced CT.14Carmona-Sanchez R. Uscanga L. Bezaury-Rivas P. Robles-Diaz G. Suazo-Barahona J. Vargas-Vorackova F. Potential harmful effect of iodinated intravenous contrast medium on the clinical course of mild acute pancreatitis.Arch Surg. 2000; 135: 1280-1284Crossref PubMed Scopus (55) Google Scholar Since prospective and randomized human studies are not available, it is reasonable to reserve contrast-enhanced CT scans for patients with severe AP, patients with smoldering AP that is slow to improve, patients with suspected local complications, and patients with an unclear etiology of the attack of AP. The use of magnetic resonance imaging (MRI) as an alternative imaging modality to CT has not been extensively studied but recently a gadolinium-enhanced dynamic MRI was found to be comparable to intravenous contrast enhanced CT for the assessment of the severity of AP.15Arvanitakis M. Delhaye M. De Maertelaere V. Bali M. Winant C. Coppens E. Jeanmart J. Zalcman M. Van Gansbeke D. Deviere J. Matos C. Computed tomography and magnetic resonance imaging in the assessment of acute pancreatitis.Gastroenterology. 2004; 126: 715-723Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar Furthermore, magnetic resonance cholangiopancreatography (MRCP) done at the same time might have the ability to identify choledocholithiasis more accurately than CT.15Arvanitakis M. Delhaye M. De Maertelaere V. Bali M. Winant C. Coppens E. Jeanmart J. Zalcman M. Van Gansbeke D. Deviere J. Matos C. Computed tomography and magnetic resonance imaging in the assessment of acute pancreatitis.Gastroenterology. 2004; 126: 715-723Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar In most centers, however, a transabdominal ultrasound and abdominal CT scan are the primary radiologic tests. Patients in whom this initial evaluation does not reveal an underlying etiology are classified as having "idiopathic" acute pancreatitis (IAP). It is in these patients where one can consider a more extensive evaluation. In most analyses, the most common explanations which are identified with a more extensive evaluation include microlithiasis, SOD dysfunction, pancreas divisum, and other congenital abnormalities, pancreatic and ampullary neoplasm, and genetic causes.16Coyle W.J. Pineau B.C. Tarnasky P.R. Knapple W.L. Aabakken L. Hoffman B.J. Cunningham J.T. Hawes R.H. Cotton P.B. Evaluation of unexplained acute and acute recurrent pancreatitis using endoscopic retrograde cholangiopancreatography, sphincter of Oddi manometry and endoscopic ultrasound.Endoscopy. 2002; 34: 617-623Crossref PubMed Scopus (133) Google Scholar, 17Venu R.P. Geenen J.E. Hogan W. Stone J. Johnson G.K. Soergel K. Idiopathic recurrent pancreatitis. An approach to diagnosis and treatment.Dig Dis Sci. 1989; 34: 56-60Crossref PubMed Scopus (164) Google Scholar, 18Kaw M. Brodmerkel Jr, G.J. ERCP, biliary crystal analysis, and sphincter of Oddi manometry in idiopathic recurrent pancreatitis.Gastrointest Endosc. 2002; 55: 157-162Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 19Guelrud M. Mujica C. Jaen D. Plaz J. Arias J. The role of ERCP in the diagnosis and treatment of idiopathic recurrent pancreatitis in children and adolescents.Gastrointest Endosc. 1994; 40: 428-436Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 20Toouli J. Di Francesco V. Saccone G. Kollias J. Schloithe A. Shanks N. Division of the sphincter of Oddi for treatment of dysfunction associated with recurrent pancreatitis.Br J Surg. 1996; 83: 1205-1210Crossref PubMed Scopus (89) Google Scholar, 21Ros E. Navarro S. Bru C. Garcia-Puges A. Valderrama R. Occult microlithiasis in 'idiopathic' acute pancreatitis Prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy.Gastroenterology. 1991; 101: 1701-1709Abstract PubMed Google Scholar Based on the current evidence and a variety of expert opinions, the following 3 management strategies can be considered in our patient with IAP: (1) expectant approach with no further testing, (2) empiric cholecystectomy, and (3) further specialized diagnostic evaluation. The strategy of no further testing in patients younger than 40 years of age is supported by two lines of evidence. The medium term recurrence rate after an initial attack of IAP is believed to be low.22Ballinger A.B. Barnes E. Alstead E.M. Fairclough P.D. Is intervention necessary after a first episode of acute idiopathic pancreatitis?.Gut. 1996; 38: 293-295Crossref PubMed Scopus (63) Google Scholar In a study from the United Kingdom, 31 patients with a single episode of IAP were evaluated. All patients underwent an evaluation consisting of history, physical examination, routine laboratory tests, and US, CT, or both. About two-thirds of these patients also underwent ERCP, although none had bile analysis, SOD manometry, or sphincterotomy. During a median follow-up of 36 months only one patient had recurrent pancreatitis, leading to a recommendation that extensive evaluation of unexplained AP be delayed until the second attack. The second line of evidence favoring a conservative approach is that the incidence of malignant neoplasm as the underlying cause of AP is low in patients < 40 years of age. In a study presented only in abstract form, Choudari et al found that only 3% patients with AP younger that 40 years had a pancreatic neoplasm. In contrast 21% of patients aged 40 to 60, and 25% of patients aged older than 60 years had a neoplastic process as the cause of their AP.23Choudari C.P. Fogel E.L. Sherman S. Lehman G.A. Idiopathic pancreatitis Yield of ERCP correlated with patient age.Am J Gastroenterol. 1998; 93: 1654AGoogle Scholar Based on these limited data the current consensus is that no further testing is an acceptable management strategy in young patients (< 40 years) with one mild episode of unexplained AP. If the patient is older than 40 years of age, has experienced more than one attack of AP, or the initial attack of AP was severe, further investigation or therapy is indicated. The use of empiric cholecystectomy is supported by both the high prevalence of occult microlithiasis (bile crystals) in patients with IAP and by the high false-negative rate of bile crystal analysis.21Ros E. Navarro S. Bru C. Garcia-Puges A. Valderrama R. Occult microlithiasis in 'idiopathic' acute pancreatitis Prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy.Gastroenterology. 1991; 101: 1701-1709Abstract PubMed Google Scholar, 24Marks J.W. Bonorris G. Intermittency of cholesterol crystals in duodenal bile from gallstone patients.Gastroenterology. 1984; 87: 622-627PubMed Scopus (40) Google Scholar, 25Neoptolemos J.P. Davidson B.R. Winder A.F. Vallance D. Role of duodenal bile crystal analysis in the investigation of 'idiopathic' pancreatitis.Br J Surg. 1988; 75: 450-453Crossref PubMed Scopus (90) Google Scholar Two prospective studies found a high prevalence of microlithiasis (65% to 85%) in patients with IAP,26Lee S.P. Nicholls J.F. Park H.Z. Biliary sludge as a cause of acute pancreatitis.N Engl J Med. 1992; 326: 589-593Crossref PubMed Scopus (463) Google Scholar, 21Ros E. Navarro S. Bru C. Garcia-Puges A. Valderrama R. Occult microlithiasis in 'idiopathic' acute pancreatitis Prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy.Gastroenterology. 1991; 101: 1701-1709Abstract PubMed Google Scholar and those who underwent therapy with cholecystectomy had no further attacks. A number of retrospective series, most available only in abstract form, have found occult gallstones or microlithiasis to be present in 37%–89% of patients with recurrent IAP.16Coyle W.J. Pineau B.C. Tarnasky P.R. Knapple W.L. Aabakken L. Hoffman B.J. Cunningham J.T. Hawes R.H. Cotton P.B. Evaluation of unexplained acute and acute recurrent pancreatitis using endoscopic retrograde cholangiopancreatography, sphincter of Oddi manometry and endoscopic ultrasound.Endoscopy. 2002; 34: 617-623Crossref PubMed Scopus (133) Google Scholar, 17Venu R.P. Geenen J.E. Hogan W. Stone J. Johnson G.K. Soergel K. Idiopathic recurrent pancreatitis. An approach to diagnosis and treatment.Dig Dis Sci. 1989; 34: 56-60Crossref PubMed Scopus (164) Google Scholar, 18Kaw M. Brodmerkel Jr, G.J. ERCP, biliary crystal analysis, and sphincter of Oddi manometry in idiopathic recurrent pancreatitis.Gastrointest Endosc. 2002; 55: 157-162Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 19Guelrud M. Mujica C. Jaen D. Plaz J. Arias J. The role of ERCP in the diagnosis and treatment of idiopathic recurrent pancreatitis in children and adolescents.Gastrointest Endosc. 1994; 40: 428-436Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 20Toouli J. Di Francesco V. Saccone G. Kollias J. Schloithe A. Shanks N. Division of the sphincter of Oddi for treatment of dysfunction associated with recurrent pancreatitis.Br J Surg. 1996; 83: 1205-1210Crossref PubMed Scopus (89) Google Scholar Despite these findings the prevalence of microlithiasis as a cause of IAP remains controversial. All published studies were conducted in tertiary referral centers, and the majority are retrospective case series with substantial selection bias. At present the expert consensus is that empiric cholecystectomy is a reasonable management approach in patients with IAP, particularly those with recurrent attacks of pancreatitis.27Steinberg W.M. Geenen J.E. Bradley 3rd, E.L. Barkin J.S. Controversies in clinical pancreatology. Recurrent "idiopathic" acute pancreatitis Should a laparoscopic cholecystectomy be the first procedure of choice?.Pancreas. 1996; 13: 329-334Crossref PubMed Scopus (14) Google Scholar, 28Tarnasky P.R. Hawes R.H. Endoscopic diagnosis and therapy of unexplained (idiopathic) acute pancreatitis.Gastrointest Endosc Clin N Am. 1998; 8: 13-37PubMed Google Scholar A number of specialized test are available to further attempt to define the etiology of an attack of AP (Table 3).Table 3Conditions That Can Cause Acute Pancreatitis and Specialized Test That Can Detect ThemConditionDiagnostic modalitiesAutoimmune pancreatitisAntinuclear antibody, Ig G4, ERCPBilary stones, sludge or crystalsEUS, MRCP, ERCP, Duodenal aspiration with crystal analysisCongenital anomalies (pancreas divisum, annular pancreas, anomalous pancreatobiliary junction, choledochocele)EUS, MRCP, ERCPChronic pancreatitisEUS, MRCP, ERCP, Secretin stimulation testGeneticGenetic analysis of the cystic fibrosis gene, trypsin gene, and pancreatic secretory trypsin inhibitor geneNeoplasm (pancreatic, ampullary)EUS, MRCP, ERCPSphincter of Oddi dysfunctionERCP with sphincter of Oddi manometry Open table in a new tab A number of studies have identified mutations in patients with idiopathic pancreatitis, including mutations in the genes encoding cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (Serine Protease Inhibitor Kazal Type 1 or SPINK-1), cystic fibrosis transmembrane conductance regulator (CFTR), and α1-antitrypsin.29Gorry M.C. Gabbaizedeh D. Furey W. Gates Jr, L.K. Preston R.A. Aston C.E. Zhang Y. Ulrich C. Ehrlich G.D. Whitcomb D.C. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis.Gastroenterology. 1997; 113: 1063-1068Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar, 30Witt H. Luck W. Hennies H.C. Classen M. Kage A. Lass U. Landt O. Becker M. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis.Nat Genet. 2000; 25: 213-216Crossref PubMed Scopus (873) Google Scholar, 31Cohn J.A. Friedman K.J. Noone P.G. Knowles M.R. Silverman L.M. Jowell P.S. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.N Engl J Med. 1998; 339: 653-658Crossref PubMed Scopus (830) Google Scholar Mutations in CFTR and SPINK-1, and to lesser extent PRSS1, have been most strongly implicated as underlying etiological factors in IAP.29Gorry M.C. Gabbaizedeh D. Furey W. Gates Jr, L.K. Preston R.A. Aston C.E. Zhang Y. Ulrich C. Ehrlich G.D. Whitcomb D.C. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis.Gastroenterology. 1997; 113: 1063-1068Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar, 30Witt H. Luck W. Hennies H.C. Classen M. Kage A. Lass U. Landt O. Becker M. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis.Nat Genet. 2000; 25: 213-216Crossref PubMed Scopus (873) Google Scholar, 31Cohn J.A. Friedman K.J. Noone P.G. Knowles M.R. Silverman L.M. Jowell P.S. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.N Engl J Med. 1998; 339: 653-658Crossref PubMed Scopus (830) Google Scholar The connection between α1-antitrypsin deficiency and IAP is questionable. A few case reports and one systematic study suggest that deficiency in this protease inhibitor renders the pancreas more vulnerable to injury.32Novis B.H. Young G.O. Bank S. Marks I.N. Chronic pancreatitis and alpha-1-antitrypsin.Lancet. 1975; 2: 748-749Abstract PubMed Scopus (70) Google Scholar More recent studies have found that the incidence of α1-antitrypsin mutations was similar in patients with IAP and normal controls.33Witt H. Kage A. Luck W. Becker M. Alpha1-antitrypsin genotypes in patients with chronic pancreatitis.Scand J Gastroenterol. 2002; 37: 356-359Crossref PubMed Scopus (31) Google Scholar In general, the role of genetic testing in IAP is controversial. Many of these mutations cannot even be measured by commercially available techniques (eg, most commercially available kits measure less than 100 of the known 1200 CFTR mutations). In addition, diagnosing these genetic disorders will add little to patient management since no specific therapy is available. Similarly, inadvertent disclosure of the results of genetic testing might have significant negative effects on the patient and the ability to obtain health insurance. On the other hand, one could argue that the identification of an underlying genetic cause may obviate the need for further testing, might allow more informed family planning, and might allow better surveillance for complications including pancreatic cancer. At the moment, the lack of commercially available techniques makes genetic testing a moot point. In the future, however, it is likely this will assume a more prominent role in the evaluation of patients with IAP. The decision to pursue genetic testing is one that should only be made with the advice and involvement of an experienced genetic counselor. At the current time, microlithiasis is diagnosed by bile analysis. The procedure requires stimulation with cholecystokinin, followed by aspiration of bile in the duodenum via a designated duodenal tube or an endoscope or by collection of pure bile via a biliary catheter at the time of ERCP. Although perhaps technically different, the terms microlithiasis, biliary sludge, and biliary crystals are often used interchangeably. Microlithiasis refers to stones of < 3 mm. Biliary sludge is a suspension of crystals, mucin, glycoproteins, cellular debris, and proteinaceous material. Finally, the term biliary crystals refers to isolated crystals of calcium bilirubinate, calcium carbonate, or cholesterol monohydrate. The high prevalence of biliary crystals in patients with IAP suggests that they are the most common etiology.26Lee S.P. Nicholls J.F. Park H.Z. Biliary sludge as a cause of acute pancreatitis.N Engl J Med. 1992; 326: 589-593Crossref PubMed Scopus (463) Google Scholar, 21Ros E. Navarro S. Bru C. Garcia-Puges A. Valderrama R. Occult microlithiasis in 'idiopathic' acute pancreatitis Prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy.Gastroenterology. 1991; 101: 1701-1709Abstract PubMed Google Scholar The optimal method to detect biliary crystals is yet to be determined. The sensitivity of duodenal bile aspiration via a duodenal tube is around 65% with specificity of 94%–100%.21Ros E. Navarro S. Bru C. Garcia-Puges A. Valderrama R. Occult microlithiasis in 'idiopathic' acute pancreatitis Prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy.Gastroenterology. 1991; 101: 1701-1709Abstract PubMed Google Scholar, 25Neoptolemos J.P. Davidson B.R. Winder A.F. Vallance D. Role of duodenal bile crystal analysis in the investigation of 'idiopathic' pancreatitis.Br J Surg. 1988; 75: 450-453Crossref PubMed Scopus (90) Google Scholar Several important issues limit the use of bile analysis. The test is not appropriate in those who have had previous cholecystectomy. Many patients (29%–34%) with gallstones (who all should be expected to have microlithiasis or crystals) have a negative bile analysis.21Ros E. Navarro S. Bru C. Garcia-Puges A. Valderrama R. Occult microlithiasis in 'idiopathic' acute pancreatitis Prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy.Gastroenterology. 1991; 101: 1701-1709Abstract PubMed Google Scholar, 24Marks J.W. Bonorris G. Intermittency of cholesterol crystals in duodenal bile from gallstone patients.Gastroenterology. 1984; 87: 622-627PubMed Scopus (40) Google Scholar, 25Neoptolemos J.P. Davidson B.R. Winder A.F. Vallance D. Role of duodenal bile crystal analysis in the investigation of 'idiopathic' pancreatitis.Br J Surg. 1988; 75: 450-453Crossref PubMed Scopus (90) Google Scholar The technique is not standardized, and in particular 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).34Levy M.J. Geenen J.E. Idiopathic acute recurrent pancreatitis.Am J Gastroenterol. 2001; 96: 2540-2555Crossref PubMed Google Scholar Finally, the procedure is only available at tertiary institutions. The use of bile analysis remains controversial and poorly standardized, and further research is needed.35Cohen S. Bacon B.R. Berlin J.A. Fleischer D. Hecht G.A. Loehrer Sr, P.J. McNair Jr, A.E. Mulholland M. Norton N.J. Rabeneck L. Ransohoff D.F. Sonnenberg A. Vannier M.W. National I
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