II48 Gut 1999;45(Suppl II):II48–II54 Functional disorders of the and pancreas

E Corazziari, E A ShaVer, W J Hogan, S Sherman, J Toouli

Abstract Normal gall bladder and sphincter of The term “dysfunction” defines the motor Oddi function disorders of the gall bladder and the The gall bladder and the sphincter of Oddi sphincter of Oddi (SO) without note of the (SO) act as an integrated unit to regulate bile potential etiologic factors for the diYculty flow from the liver through the biliary tract into to diVerentiate purely functional altera- the .1 The SO similarly controls pancreatic exocrine output. During fasting, Chair, Committee on tions from subtle structural changes. Dys- Functional Biliary and function of the gall bladder and/or SO hepatic bile enters the gall bladder for storage. Pancreatic Disorders, produces similar patterns of biliopancre- The gall bladder accommodates this increase Multinational Working atic and SO dysfunction may occur in in volume through receptive relaxation without Teams to Develop the presence of the gall bladder. The any significant rise in pressure and by concen- Diagnostic Criteria for symptom-based diagnostic criteria of gall trating bile to keep its volume small. The gall Functional bladder evacuates bile by smooth muscle Gastrointestinal bladder and SO dysfunction are episodes Disorders (Rome II), of severe steady pain located in the epigas- contraction, coordinated with reduced tone in Cattedra di trium and right upper abdominal quad- the SO. During fasting, about 25% of the emp- Gastroenterologia I, rant which last at least 30 minutes. Gall tying of gall bladder contents occurs periodi- Clinica Medica II, cally every 100–120 minutes, mediated by Università “La bladder and SO dysfunctions can cause significant clinical symptoms but do not motilin, which acts via vagal cholinergic nerves Sapienza,” and is synchronized with the migratory motor Rome, Italy explain many instances of biliopancreatic 2 E Corazziari type of pain. The syndrome of functional complex of the intestine. Eating initiates over abdominal pain should be diVerentiated 75% of gall bladder emptying through neural Co-Chair, Committee from gall bladder and SO dysfunction. In (cephalic and local gastroduodenal reflexes) on Functional Biliary and hormonal (predominantly cholecystokinin and Pancreatic the diagnostic workup, invasive investiga- tions should be performed only in the (CCK) acting via cholinergic nerves) Disorders, influences.3 Non-adrenergic, non-cholinergic Multinational Working presence of compelling clinical evidence inhibitory nerves produce SO relaxation Teams to Develop and after non-invasive testing has yielded through the release of vasoactive intestinal Diagnostic Criteria for negative findings. Gall bladder dysfunction Functional peptide (VIP) and nitric oxide, acting as post- is suspected when laboratory, ultrasono- Gastrointestinal ganglionic neurotransmitters.4 The neural sup- graphic, and microscopic bile examination Disorders (Rome II), ply to the biliary tract includes vagal eVerent have excluded the presence of Department of nerves releasing acetylcholine, sympathetic fib- Medicine, and other structural abnormalities. The ers releasing norepinepherine, and sensory University of Calgary, finding of decreased gall bladder emptying nerves containing substance P. Sensory fibers Calgary, Alberta, at cholecystokinin-cholescintigraphy is the Canada influence the neural response, acting via the only objective characteristic of gall blad- E A ShaVer vagus through central reflexes.5 Derangements der dysfunction. Symptomatic manifesta- of any of these components may lead to inter- Division of tion of SO dysfunction may be mittent upper abdominal pain, transient eleva- and accompanied by features of biliary ob- tions of liver or pancreatic enzymes, common , struction (biliary-type SO dysfunction) or Milwaukee, WI, USA dilatation, or episodes of . W J Hogan significant elevation of pancreatic en- zymes and pancreatitis (pancreatic-type Definition of gall bladder and sphincter SO dysfunction). Biliary-type SO dysfunc- Division of of Oddi dysfunction Gastroenterology and tion occurs more frequently in post- Motor dysfunction of the gall bladder and SO Hepatology, cholecystectomy patients who are Indiana University has long been suspected as a major feature of categorized into three types. Types I and II, several clinical entities that manifest with a School of Medicine, but not type III, have biochemical and Indianapolis, IN, USA similar pattern of upper abdominal pain (table S Sherman cholangiographic features of biliary ob- 1). Unlike other functional gastrointestinal dis- struction. Pancreatic-type SO dysfunction orders, however, abnormalities are beginning Gastrointestinal is less well classified into types. When non- Surgical Unit, to be identified by new technologies, although invasive investigations and endoscopic ret- in many instances a cause-and-eVect relation- Flinders Medical rograde cholangiopanreatography show Centre, ship has not been substantiated. Clinical SA, Australia no structural abnormality, manometry of symptoms may not coincide temporally with J Toouli both biliary and pancreatic sphincter may the demonstrated abnormality. Further, im- be considered. paired gall bladder emptying occurs in many Correspondence to: Eldon (Gut 1999;45(Suppl II):II48–II54) 6 ShaVer, MD, Professor and patients with cholesterol gallstones, yet most Head, Department of Keywords: biliary tract disease; sphincter of Oddi Medicine, Foothills Medical Centre, 1403 29th Street dysfunction; disease; pancreatitis; endoscopic Abbreviations used in this paper: SO, sphincter of NW, Calgary, Alberta T2N retrograde cholangiopancreatography; cholescintigraphy; Oddi; CCK, cholecystokinin; VIP, vasoactive intestinal 2T9, Canada. Email: endoscopic ultrasonography; cholecystokinin; magnetic peptide; ERCP, endoscopic retrograde [email protected] resonance cholangiopancreatography; Rome II cholangiopancreatography. Functional disorders of the biliary tract and pancreas II49

Table 1 Functional gastrointestinal disorders the gall bladder and SO” without attempting to attribute its cause(s) or to identify often subtle A. Esophageal disorders morphological changes. This classification A1. Globus A2. Rumination syndrome consists of: A3. Functional chest pain of presumed esophageal origin (1) gall bladder dysfunction, and A4. Functional heartburn A5. Functional dysphagia (2) SO dysfunction, which may be subdivided A6. Unspecified functional esophageal disorder into: (a) biliary-type and (b) pancreatic- B. Gastroduodenal disorders type. B1. Functional dyspepsia B1a. Ulcer-like dyspepsia The following clinical observations should B1b. Dysmotility-like dyspepsia be considered with regard to gall bladder and B1c. Unspecified (non-specific) dyspepsia SO dysfunction: B2. Aerophagia B3. Functional vomiting + gall bladder and SO dysfunction manifest C. Bowel disorders symptomatically with the same type of pain; C1. although the diagnosis of SO dysfunction is C2. Functional abdominal bloating + C3. Functional usually made following cholecystectomy, SO C4. Functional dysfunction can manifest clinically in pa- C5. Unspecified functional bowel disorder tients with an intact biliary tract; D. Functional abdominal pain D1. Functional abdominal pain syndrome + psychosocial aspects appear to be variably D2. Unspecified functional abdominal pain interrelated with gall bladder and SO E. Biliary disorders E1. Gall bladder dysfunction dysfunction; E2. Sphincter of Oddi dysfunction + the syndrome of chronic functional abdomi- F. Anorectal disorders nal pain may manifest with clinical charac- F1. Functional fecal incontinence F2. Functional anorectal pain teristics similar to biliopancreatic type of F2a. syndrome pain. F2b. Proctalgia fugax F3. Pelvic floor dyssynergia G. Functional pediatric disorders E1. Gall bladder dysfunction G1. Vomiting G1a. Infant regurgitation The central symptom of gall bladder dysfunc- G1b. Infant rumination syndrome tion is biliary-type pain. Currently, the only G1c. objective characteristic is decreased gall blad- G2. Abdominal pain G2a. Functional dyspepsia der emptying. Available techniques have not G2b. Irritable bowel syndrome clarified its basis (perhaps there is more than G2c. Functional abdominal pain one cause) and cannot exclude other entities G2d. Abdominal migraine G2e. Aerophagia such as impaired filling or an overly sensitive G3. Functional diarrhea gall bladder. G4. Disorders of defecation G4a. Infant dyschezia G4b. Functional constipation EPIDEMIOLOGY G4c. Functional fecal retention Gallstones are the most common aZiction of G4d. Non-retentive fecal soiling the gall bladder, but only 10–20% of patients ever develop symptoms.10 Further, there is no association with dyspepsia.11 The frequency of (over 80%) never develop symptoms. Struc- biliary pain in those without gallstones may be tural changes, particularly those indicative of as high as 7.6% of men12 and 20.7% of chronic inflammation, may not necessarily cor- women,13 or as low as 2.4% overall, as reported relate with impaired emptying in patients with in an ultrasonographic survey.14 .7 The presumed mechanism for biliary pain is obstruction leading to disten- sion and inflammation. This might result from DIAGNOSTIC CRITERIA incoordination between the gall bladder and Episodes of severe steady pain located in the either the cystic duct or the SO due to epigastrium and right upper quadrant, and increased resistance or tone. Fibrosis and all of the following: inflammation also can aVect the SO, but any (1) Episodes last 30 minutes or more; clinical relevance is unclear. Rather, for both (2) Symptoms have occurred on one or the gall bladder and SO, motor contraction, more occasions in the previous 12 sensory aVerents, and obstruction/ months; inflammation all likely play a role in biliary- (3) The pain is steady and interrupts daily type pain. Central projections from visceral activities or requires consultation with a nociceptors to the thalamus and cortex might physician; lead to a more excitable state with (4) There is no evidence of structural (severe pain evoked by mildly painful stimuli). abnormalities to explain the symptoms; Persistent central excitability might then result and in allodynia where innocuous stimuli produce (5) There is abnormal gall bladder func- pain.8 The “hypersensitive biliary tract” may tioning with regard to emptying. exist,9 but the anatomy of the biliary tract pre- cludes ready access to assess this hypothesis The presence of biliary sludge implies gall scientifically. bladder dysfunction in the form of stasis from Motor dysfunction currently is the most impaired emptying but may not necessarily eVectively studied of the sources of disorders; it explain the pain. In addition the pain may be is the only available measure of gall bladder associated with one or more of the following: and SO dysfunction. We therefore have and vomiting; pain radiating to the back adopted the term “dysfunctional disorders of and/or right interscapular region; onset after II50 Corazziari, ShaVer, Hogan, et al

meals; and/or awakens the patient at night. In Tests for gall bladder dysfunction some, these symptoms may be superimposed CCK–cholescintigraphy assessment of gall bladder on a background of low grade chronic abdomi- emptying—This study continuously monitors nal pain of unknown etiology. the hepatic excretion of a radiopharmaceutical into the gall bladder and duodenum, using computer assistance to quantitate changes in RATIONALE FOR CHANGES IN DIAGNOSTIC radioactivity over the gall bladder. Filling of CRITERIA the gall bladder with radionuclide indicates There are two major changes compared with patency of the cystic duct. Gall bladder the Rome I diagnostic criteria. The first refers emptying is expressed as the gall bladder ejec- to the specification of the duration, number of tion fraction, the percentage decrease in net episodes of pain, and the time within which gall bladder counts following CCK infusion they occur: (CCK-8 slowly infused at 20 ng/kg over 30 (1) 30 minutes has been more firmly estab- minutes). Reduced emptying, which defines lished in the literature as the minimum gall bladder dysfunction, can arise from either duration of a biliary “colic”; depressed gall bladder contraction or in- (2) even a single pain episode may be so severe creased resistance such as elevated tone in the as to justify diagnostic investigation irre- SO. Furthermore, several other conditions spective of the number of episodes, and that do not necessarily present with biliary (3) the frequency of biliary pain may be so colic can be associated with reduced gall blad- irregular that a time window of only three der emptying. These range from intrinsic gall months has been considered too restric- bladder disease (stones, ) to neu- tive. ral and metabolic disorders, drugs, and even The second change is point 5, the specifica- the irritable bowel syndrome. Although tion of the only established functional abnor- biliary-type pain is rarely elicited, the test mality. appears to be a marker of this biliary disorder, based on evidence of the beneficial eVect of CLINICAL EVALUATION cholecystectomy. Screening tests Transabdominal ultrasonography—This test Laboratory—Tests of liver biochemistries and measures gall bladder volume, which if fol- pancreatic enzymes must be normal. lowed serially after a stimulus (meal or CCK), The following tests are necessary to elimi- reflects emptying. The technique is operator nate calculous biliary disease, which can dependent and the results may not be repro- produce similar symptoms. ducible in diVerent centers.18 Ultrasonographic Ultrasonography—Transabdominal ultrasonog- assessment of gall bladder emptying is cur- raphy of the upper abdomen is mandatory. The rently not the standard for gall bladder biliary tract and pancreas should be normal dysfunction. and gallstones or sludge absent. Ultrasonogra- Pain provocation test—Stimulation tests with phy readily detects stones equal to or greater CCK to duplicate biliary pain have been used than 3–5 mm in diameter or biliary sludge historically as a diagnostic investigation. Such within the gall bladder, but it has a low tests have low sensitivity and specificity sensitivity for smaller stones or biliary microc- in selecting patients with gall bladder rystals. It also has a low yield for stones within dysfunction who respond to therapy. This the . Endoscopic ultrasonog- may relate to problems in the subjective raphy seems to be more sensitive than tra- assessment of pain and the use of bolus injec- ditional transabdominal ultrasonography in tions of CCK, which can induce intestinal detecting microlithiasis (tiny stones <3 mm) contractions. and sludge within the biliary tract, but the rec- ommendation for its inclusion in standard Diagnostic workup workups requires further evaluation. Biliary tract symptoms should be evaluated by Microscopic bile examination—This procedure is liver biochemistry, pancreatic enzymes, and necessary to exclude microlithiasis as a cause. ultrasound examination of the abdomen. As a Gall bladder bile can be obtained directly at the general recommendation we suggest that inva- time of endoscopic retrograde cholangiopan- sive investigations should be withheld in those creatography (ERCP) or by aspiration from the patients in whom episodes are infrequent and duodenum following stimulation (e.g., CCK-8 not accompanied by increased liver function

5 ng/kg i.v. over 10 minutes, or 50 ml MgSO4 tests. instilled into the duodenum). Two types of + If no abnormal findings are detected, CCK– deposits may be evident: (1) cholesterol micro- cholescintigraphy should be used to assess crystals, which are birefringent and rhomboid gall bladder emptying. Abnormal gall blad- shaped, best visualized by polarizing der emptying (<40% ejection) indicates gall microscopy.15 Their presence provides a high bladder dysfunction. diagnostic accuracy for microlithiasis16; and (2) + If there is no obvious cause for impaired bilirubinate granules, which appear as red- emptying, cholecystectomy is appropriate brown deposits under conventional light mi- treatment. croscopy. + If gall bladder emptying is normal, bile for Endoscopy—In the presence of normal labora- microscopic examination to detect choles- tory and ultrasonographic findings, endoscopy terol microcrystals and bilirubinate can be is usually indicated to exclude upper gastro- obtained by duodenal drainage, at the time intestinal diseases. of gastrointestinal endoscopy or during Functional disorders of the biliary tract and pancreas II51

ERCP. Magnetic resonance cholangiogra- ders and Functional abdominal pain) manifests phy or endoscopic ultrasound, where avail- itself as biliary pain is higher in type III patients able, can be performed to detect lithiasis. and less likely in type I. + If gall bladder emptying is normal, ERCP should be considered. In the absence of E2b. Pancreatic-type SO dysfunction common bile duct stones or other abnor- Sphincter of Oddi dysfunction is less easily malities, SO manometry should be classified into types. In its more obvious form considered if clinically indicated. Evidence (like biliary-type I) pancreatic-type SO dys- of SO dysfunction is an indication for treat- function may present with classic pancreatitis ment, which may include sphincterotomy. with epigastric pain, which often radiates to the back, and with evidence of elevated serum APPROACH TO TREATMENT amylase or lipase. The absence of the tra- Medical therapy remains theoretical. It might ditional causes of pancreatitis (no stones or take the form of: (1) altering gall bladder motor alcohol misuse) often yields the label of function (e.g., use of motility agents which idiopathic recurrent pancreatitis. In a less obvi- enhance gall bladder contractility19 or ursode- ous form (like biliary-type III SO dysfunction), oxycholic acid which worsens motility yet less- the pain is similar but there is no increase in ens the likelihood of biliary pain20); (2) reduc- pancreatic enzymes; in many of these patients ing visceral hyperalgesia or inflammation (e.g., the symptomatology may be a manifestation of with non-steroidal anti-inflammatory drugs21); the syndrome of functional abdominal pain. or (3) as a last resort, cholecystectomy. CCK– cholescintigraphy will identify those patients EPIDEMIOLOGY The prevalence of symptoms suggesting SO with impaired emptying. The challenge is to dysfunction is about 1.5% of patients after interpret the subgroup that will benefit from cholecystectomy, being more frequent in treatment. Laparascopic cholecystectomy re- women.23 From another perspective, SO dys- tains a role in the treatment of gall bladder function appears in less than 1% of patients dysfunction, although favorable outcomes may after cholecystectomy and in 14% of a selected deteriorate with time, a potential placebo effect group of patients complaining of postcholecys- of surgery. tectomy symptoms.24 In patients with idio- pathic recurrent pancreatitis, manometric evi- E2. Sphincter of Oddi dysfunction dence of SO dysfunction was found to vary Sphincter of Oddi dysfunction is the term used between 39 and 90%.25 26 SO dysfunction can to define motility abnormalities of the SO. involve abnormalities in the biliary sphincter, Because of its strategic position at the duodenal pancreatic sphincter, or both. The true fre- junction of the biliary duct and pancreatic quency thus depends on whether one or both duct, SO dysfunction may result in either sphincters are studied. biliary or pancreatic disorders. SO dysfunction may be present in patients with an intact biliary DIAGNOSTIC CRITERIA tract, but it has been more frequently reported Episodes of severe steady pain located in the following cholecystectomy. epigastrium and right upper quadrant, and all of the following: E2a. Biliary-type SO dysfunction (1) Episodes last 30 minutes or more; Patients present with intermittent episodes of (2) Symptoms have occurred on one or biliary-type pain, sometimes accompanied by more occasions in the previous 12 biochemical features of transient biliary tract months; obstruction: elevated serum aminotransferases, (3) The pain is steady and interrupts daily alkaline phosphatase, or conjugated bilirubin. activities or requires consultation with a These postcholecystectomy patients have been physician; and arbitrarily classified according to clinical pres- (4) There is no evidence of structural entation, laboratory results, and ERCP abnormalities to explain the symptoms. findings22: + Patients with biliary-type I SO dysfunction In addition the pain may be associated with present with pain, elevated liver function one or more of the following: tests documented on two or more occasions, + The diagnosis is supported by elevated delayed contrast drainage, and a dilated serum aminotransferases, alkaline phos- common bile duct with a corrected diameter phatase, or conjugated bilirubin, and/or equal to or greater than 12 mm at ERCP. pancreatic enzymes (amylase/lipase). + Type II patients present with pain and only + Acute recurrent pancreatitis can indicate one or two of the previously mentioned cri- pancreatic SO dysfunction. teria. Other clinical features that may be associated + Type III patients have only recurrent with the pain episodes are: nausea and biliary-type pain and none of the above cri- vomiting; pain radiating to the back and/or teria. right interscapular regions (biliary) and/or pain The predictability of SO dysfunction varies partially alleviated by bending forward (pan- among these groups, being highest in types I creatic); onset after meals; awakens the patient (65–95%) and II (50–63%), but less so in type at night. III (12–28%). Conversely, the probability that Sphincter of Oddi dysfunction may exist in the syndrome of chronic functional abdominal the presence of an intact biliary tract with the pain (see chapters on Functional bowel disor- gall bladder intact. As the symptoms of SO or II52 Corazziari, ShaVer, Hogan, et al

Table 2 Pressure profile of the sphincter of Oddi measured at the common bile (CBD) and Choledochoscintigraphy—Following cholecys- pancreatic (PD) ducts tectomy, SO tone mainly regulates bile delivery into the duodenum. Dysfunction of the sphinc- Normal* CBD Abnormal† PD CBD and PD ter becomes manifest by a delay in the Duct pressure (mm Hg) 7.4 (1.7) 8.0 (1.6) disappearance of radiopharmaceutical markers Basal pressure (mm Hg) 16.2 (5.8) (6–25) 17.3 (5.8) (8–26) >40 29 Phasic contractions of bile from the biliary tract, or a prolonged Amplitude (mm Hg) 136.5 (25.9) (82–180) 127.5 (21.5) (90–160) >350 transit of radiolabeled bile from the hepatic Duration (seconds) 4.7 (0.9) (3–6) 4.8 (0.7) (4–6) hilum to the duodenum.30 Choledochoscinti- Frequency (/minute) 5.7 (1.4) (3–10) 5.8 (1.5) (3–10) >7 Propagation sequence (%) graphy is a useful screening method to select Simultaneous 55 (10–100) 53 (10–90) patients after cholecystectomy, in whom SO Antegrade 34 (0–70) 35 (10–70) manometry might reveal abnormalities. Retrograde 11 (0–40) 12 (0–40) >50

*Values are mean (SD); ranges are given in parentheses.31 †Abnormal values for the CBD.32 Invasive tests Endoscopic retrograde cholangiopancreatography— gall bladder dysfunction cannot be readily Certain radiologic features at ERCP such as a separated, the diagnosis of SO dysfunction is common bile duct diameter exceeding 12 mm made commonly following cholecystectomy, or and delayed emptying of contrast media (>45 less frequently after proper investigations have minutes) suggest SO dysfunction. Additional excluded gall bladder abnormalities. features are a dilated pancreatic duct (>5 mm) and delayed emptying of contrast media from RATIONALE FOR CHANGES IN DIAGNOSTIC the pancreatic duct (>10 minutes). However, CRITERIA variables such as premedication, lack of stand- There is one major change compared with the ardization, and the patient’s posture limit their Rome I diagnostic criteria. This refers to the value. specification of the duration, number of SO manometry—Perendoscopic manometry episodes of pain, and the time within which identifies the sphincter as the zone of elevated they occur: resting pressure between the duct (pancreatic (1) 30 minutes has been more firmly estab- or choledochal) and the duodenum. Phasic lished in the literature as the minimum waves are superimposed (table 2).31 Manomet- duration of a biliary “colic”; ric alterations of the SO include: increased (2) even a single pain episode may be so severe basal pressure, increased amplitude of phasic as to justify diagnostic investigation irre- waves, a paradoxical response to CCK, in- spective of the number of episodes, and creased frequency of phasic waves, and an (3) the frequency of biliary pain may be so increased number of retrograde waves.24–27 32 irregular that a time window of only three Elevated basal SO pressure is diagnostic of months has been considered too restric- either stenosis or spasm of the sphincter. With tive. sphincteric spasm, SO pressure decreases after administering a smooth muscle relaxant. CLINICAL EVALUATION The only method that can directly assess the Diagnostic workup motor function of the SO is manometry. This As a general recommendation we suggest that technique is diYcult to perform and interpret, invasive investigations should be withheld in is not widely available, and is invasive with those patients in whom episodes are infrequent potential complications. Because SO dysfunc- and not accompanied by increased liver tion is relatively uncommon, less invasive function tests or pancreatic enzymes. Compli- procedures should therefore be considered first. cations from invasive procedures such as ERCP and SO manometry are more frequent Screening tests in patients with SO dysfunction and when per- Liver biochemistry—A transient but significant formed by inexperienced endoscopists. The elevation of liver enzymes and/or bilirubin in following recommendations apply only to close temporal relation to at least two episodes 27 skilled endoscopists, preferably in referral of biliary pain is suspect for SO dysfunction. centers. Pancreatic enzymes—A significant elevation of either amylase or lipase in close temporal rela- tion to pancreatic pain is suggestive of Biliary-type SO dysfunction— pancreatitis due to SO dysfunction. + The evaluation of biliary pain in patients Pain provocative tests—Use of morphine (± without gall bladders begins with laboratory prostigmine) historically to detect SO dysfunc- analyses of liver function and pancreatic tion was greatly limited by sensitivity and enzymes, plus elimination of potential struc- specificity.27 tural causes by: transabdominal ultrasound, Ultrasonographic assessment of duct diameter— analysis of bile for microcrystals, magnetic The common bile duct is normally 6 mm or resonance cholangiography, and endoscopic less.28 A dilated duct may indicate resistance to ultrasound (where available), and ERCP, bile flow through the SO but is not diagnostic depending upon the circumstances of the as this is evident in 34% of asymptomatic patient and the resources available. cholecystectomized subjects. The value of a + Choledochoscintigraphy is a useful screen- fatty meal or CCK test to unmask a partially ing test before SO manometry. obstructed bile duct has not gained acceptance + Patients with type I SO dysfunction may and neither has secretin stimulation for SO undergo endoscopic sphincterotomy with- pancreatic dysfunction. out SO manometry. SO manometry is Functional disorders of the biliary tract and pancreas II53

recommended in type II and could be tion. The even higher complication rate with considered in type III dysfunction. hydrostatic balloon dilatation and placement of + If SO manometry is normal, look for causes biliary (or pancreatic) stents for temporary pain other than SO dysfunction. relief does not support their use. + SO stenosis should be treated by endoscopic For pancreatic-type SO dysfunction, sever- sphincterotomy. ance of the pancreatic sphincter, not merely + In SO dyskinesia, a trial of drug therapy may biliary sphincterotomy, may be necessary for a be in order. successful outcome. The surgical approach is For patients with an intact gall bladder, the via transduodenal sphincteroplasty and pan- workup is part of the same diagnostic algo- creatic duct septoplasty, yielding 70% improve- rithm for gall bladder dysfunction. ment with a low risk of pancreatitis but a high morbidity of 30%.36 Endoscopic pancreatic Pancreatic-type SO dysfunction— sphincterotomy is another approach under + When ERCP demonstrates no structural investigation. All such approaches require abnormality, manometry of both biliary and further study. pancreatic sphincter is indicated. + Finding biliary SO dysfunction leads to an Conclusion endoscopic biliary sphincterotomy. Motility disorders of the gall bladder and SO + For pancreatic SO dysfunction alone or with can cause significant clinical symptoms but are biliary SO dysfunction, standard therapy is not likely to explain many instances of biliary operative sphincteroplasty and pancreatic pain. Clearly, elucidation of the basis for such septoplasty. Combined endoscopic biliary dysmotility and the detection of a putative and pancreatic sphincterotomy is undergo- hypersensitive biliary tract37 should sharpen our ing investigation. diagnostic tools, expand therapeutic options, and benefit those with this disabling problem. TREATMENT The therapeutic approach in patients with SO We thank the following reviewers for their critique of the manu- scripts and their suggestions: D A Drossman, D Festi, P Portin- dysfunction aims to reduce the resistance to the casa, A Slivka, J Svanvik. flow of bile or pancreatic juice. 1 Ryan JP. Motility of the gallbladder and biliary tree. In: Johnson LR, ed. Physiology of the .New Pharmacotherapy York: Raven Press, 1987:695–722. Some therapeutic agents have potential but 2 Stolk MF, van Erpecum KJ, Smout AJ, et al. Motor cycles there is limited evidence for their therapeutic with phase III in antrum are associated with high motilin levels and prolonged gallbladder emptying. Am J Physiol usefulness. 1993;264:G596–600. Hormones such as CCK and glucagon can 3 Takahashi T, May D, Owyang C. Cholinergic dependence of + gallbladder response to cholecystokinin in the guinea pig in transiently reduce SO tone. vivo. Am J Physiol 1991;261:G565–9. Calcium channel blockers such as 4 Pauletzki JG, Sharkey KA, Davison J, et al. Involvement of + L-arginine-nitric oxide pathways in neural relaxation of the at 10–20 mg p.o. decreases the SO pressure sphincter of Oddi. Eur J Pharmacol 1993;232:263–70. and lessens phasic contractions in biliary 5 Mawe G. Advances in the neurophysiology of the gallblad- der. In: Holle GE, Wood JD, eds. Advances in the innervation dyskinesia, benefiting patients with type II of the gastrointestinal tract. Munich: Elsevier Science SO dysfunction.33 Publishers, 1992:181–93. 6 Pomeranz IS, ShaVer EA. Abnormal gallbladder emptying + Nitrates decrease sphincteric pressure and in a subgroup of patients with gallstones. Gastroenterology can alleviate the symptoms, at least in the 1985;88:787–91. 34 7 Westlake PJ, Hershfield NB, Kelly JK, et al. Chronic right short term. upper quadrant pain without gallstones: does HIDA scan , a potent inhibitor of predict outcome after cholecystectomy? Am J Gastroenterol + 1990;85:986–90. acetylcholine release, when injected into the 8 Cervero F, Laird JMA. From acute to . Mecha- sphincter reduces its pressure, improves bile nisms and hypothesis. Prog Brain Res 1996;110:3–15. 9 Caroli J. Etude des dyskinesie biliares [thesis]. Toulouse, flow, and provides some symptomatic France: Imprimerie du Sud, 1945. relief.35 10 Gracie WA, RansohoV DF. The natural history of silent gallstones. The innocent gallstones is not a myth: N Engl J Such medical therapies have several draw- Med 1982;307:798–800. backs. Calcium channel blockers and nitrates 11 Kraagg N, Thijs C, Knipschild P. Dyspepsia–how noisy are gallstones? A meta-analysis of epidemiologic studies of bil- have significant side eVects, whereas smooth iary pain, dyspeptic symptoms, and food intolerance. Scand muscle relaxants are unlikely to be of any benefit J Gastroenterol 1995;30:411–21. 12 GREPCO (The Rome group for epidemiology and preven- in patients with SO stenosis. Responses tend to tion of cholelithiasis). The epidemiology of gallstone be transient and long term reports are lacking. disease in Rome, Italy. I. Prevalence data in men. Hepatol- ogy 1988;8:904–6. 13 GREPCO (Rome group for epidemiology and prevention of cholelithiasis). Prevalence of gallstone disease in an Italian Sphincterotomy adult female population. Am J Epidemiol 1984:119:796– Endoscopic sphincterotomy is the most widely 805. 14 Barbara L, Sama C, Morselli Labate AM, et al. A population used therapeutic procedure for patients with study on the prevalence of gallstone disease: the Sirmione biliary-type SO dysfunction, being less expen- Study. Hepatology 1987;7:913–17. sive and having lower morbidity than transduo- 15 Juniper K, Burson EN. Biliary tract studies II. The significance of biliary crystals. Gastroenterology 1957;32: denal surgery. Endoscopic sphincterotomy pro- 175–211. 16 Buscail L, Escourrou J, Delvaux M, et al. Microscopic vides symptomatic relief in 55–95% of patients. examination of bile directly collected during endoscopic The variable outcomes reflect the diVerent cannulation of the papilla. Utility in suspected microlithi- criteria used, the methods of data collection asis. Dig Dis Sci 1992;37:116–20. 17 Yap L, Wycherley AG, Morphett AD, et al. Acalculous (retrospective v prospective), and the techniques biliary pain. Cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology used to determine benefit. Pancreatitis in 1991;101:786–93. 5–16% is the most common short term compli- 18 Barr RG, Agnesi JN, Schaub CR. Acalcolous . US evaluation after slow-infusion cholecystokinin cation of endoscopic sphincterotomy, a rate stimulation in symptomatic and asymptomatic adults. higher than that for common duct stone extrac- Radiology 1997;204:105–11. II54 Corazziari, ShaVer, Hogan, et al

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