Gallbladder and Sphincter of Oddi Disorders - Rome and Sphincter of Oddi Disorders Peter B. Cotton,1...

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Transcript of Gallbladder and Sphincter of Oddi Disorders - Rome and Sphincter of Oddi Disorders Peter B. Cotton,1...

  • Gastroenterology 2016;150:14201429



    Gallbladder and Sphincter of Oddi Disorders

    Peter B. Cotton,1 Grace H. Elta,2 C. Ross Carter,3 Pankaj Jay Pasricha,4

    Enrico S. Corazziari5

    1Medical University of South Carolina, Charleston, South Carolina; 2University of Michigan, Ann Arbor, Michigan; 3GlasgowRoyal Infirmary, Glasgow, Scotland; 4Johns Hopkins School of Medicine, Baltimore, Maryland; and 5Universita La Sapienza,Rome, Italy

    The concept that motor disorders of the gallbladder, cysticduct, and sphincter of Oddi can cause painful syndromes isattractive and popular, at least in the United States. How-ever, the results of commonly performed ablative treat-ments (eg, cholecystectomy and sphincterotomy) are notuniformly good. The predictive value of tests that are oftenused to diagnose dysfunction (eg, dynamic gallbladderscintigraphy and sphincter manometry) is controversial.Evaluation and management of these patients is madedifficult by the fluctuating symptoms and the placebo effectof invasive interventions. A recent stringent study hasshown that sphincterotomy is no better than sham treat-ment in patients with post-cholecystectomy pain and littleor no objective abnormalities on investigation, so that theold concept of sphincter of Oddi dysfunction type III is dis-carded. Endoscopic retrograde cholangiopancreatographyapproaches are no longer appropriate in that context. Thereis a pressing need for similar prospective studies to providebetter guidance for clinicians dealing with these patients.We need to clarify the indications for cholecystectomy inpatients with functional gallbladder disorder and the rele-vance of sphincter dysfunction in patients with some evi-dence for biliary obstruction (previously sphincter of Oddidysfunction type II, now called functional biliary sphincterdisorder) andwith idiopathic acute recurrent pancreatitis.

    Keywords: Cholecystectomy; Biliary Pain; Post-CholecystectomyPain; Sphincter Manometry; Sphincterotomy; IdiopathicPancreatitis; Endoscopic Retrograde Cholangiopancreatography.

    unctional disorders of the gallbladder (GB) and the

    Fsphincter of Oddi (SO) are controversial topics. Theyhave gone by a variety of names, including acalculous biliarypain, biliary dyskinesia, GB dysmotility, and SO (or ampul-lary) stenosis. This articles builds on the Rome IIIconsensus,1 recognizing that the evidence base is slim. Thisarticles does not cover the anatomy and physiology, whichare well described elsewhere.

    Abbreviations used in this paper: CCK-CS, cholecystokinin-stimulatedcholescintigraphy; ERCP, endoscopic retrograde cholangiopancreatog-raphy; EUS, endoscopic ultrasound; FGBD, functional gallbladder disor-der; GB, gallbladder; GBEF, gallbladder ejection fraction; MRCP, magneticresonance cholangiopancreatography; SO, sphincter of Oddi; SOD,sphincter of Oddi dysfunction.

    Most current article

    2016 by the AGA Institute0016-5085/$36.00

    Biliary PainThe concept that disordered function of the GB and SO

    can cause pain is based mainly on the fact that manypatients have biliary-type pain in the absence of recognizedorganic causes, and that some apparently are cured byremoval of the GB or ablation of the sphincter.

    E1. Diagnostic Criteria for Biliary Pain

    Pain located in the epigastrium and/or right upperquadrant and all of the following:

    1. Builds up to a steady level and lasting 30 minutesor longer

    2. Occurring at different intervals (not daily)

    3. Severe enough to interrupt daily activities or leadto an emergency department visit

    4. Not significantly (

  • May 2016 Gallbladder and Sphincter of Oddi Disorders 1421

    not explained by a clearly identified mechanism or by astructural alteration, we use the term functional gallbladderdisorder (FGBD) to describe patients with biliary pain andan intact GB without stones or sludge.

    E1a. Diagnostic Criteria for Functional GallbladderDisorder






    1. Biliary pain

    2. Absence of gallstones or other structuralpathology

    Supportive Criteria

    1. Low ejection fraction on gallbladder scintigraphy

    2. Normal liver enzymes, conjugated bilirubin, andamylase/lipase

    Since the diagnosis is primarily one of exclusion, theprevalence depends on the rigor of investigation. Ultraso-nography is the usual primary investigation, but endoscopicultrasound (EUS) is more sensitive for detecting smallstones and biliary sludge, and can also detect small tumors,and subtle changes of chronic pancreatitis.

    The only change from Rome III is that normal liver andpancreatic enzymes have been moved to the supportivecategory. There can be other reasons for elevated liver en-zymes, like fatty liver disease, that do not rule out GBdysfunction. We have also added a low ejection fraction onGB scintigraphy as supportive. It is not required for thediagnosis, nor is it specific for the diagnosis when abnormal.2

    EpidemiologyBiliary pain is a common clinical problem, and cholecys-

    tectomy is a frequent operation. The number and proportiondone for FGBD seems to be increasing in the United States,where case series now list it as the indication forcholecystectomy in 10%20% of adults2,3 and in 10%50%

    Figure 1. Potential etio-logical pathways and clin-ical outcomes in patientswith biliary dyskinesia

    of children.4 FGBD is rarely diagnosed outside the UnitedStates.5

    PathophysiologyFGBD is often diagnosed by a low gallbladder ejection

    fraction (GBEF) at cholecystokinin-stimulated cholescintig-raphy (CCK-CS). Although the relationship between GBEF andclinical outcome remains unclear, gallbladder dysmotilitymay still play a role in the pathogenesis of symptoms, bypromoting gallbladder inflammation, which is commonlyfound. Microlithiasis is associated with a delayed ejectionfraction on scintigraphy.6 Investigators have found multipledefects in gallbladder contractility, including spontaneousactivity and abnormal responses to both CCK and neuralstimulation.7 A vicious cycle of stasis and inflammation existsin the GB. Some patients may have intrinsic defects incontractility, and subtle defects in bile composition may alsoplay a role. Studies have shown elevated sphincter of Oddi(SO) pressures in patients with GB dyskinesia, but withoutcorrelation between GBEF and SO pressure.8 GB dysfunctionmay represent a more generalized dysmotility, as in irritablebowel syndrome and chronic constipation, and perhapsgastroparesis.9 Experimental evidence has implicated severalmolecules that can link inflammation to motility, the mostimportant of which may be prostaglandin E2 (PGE2).10,11

    Possible etiological mechanisms and outcomes in patientswith biliary dyskinesia are illustrated in Figure 1.

    Clinical EvaluationGB stones should be excluded by ultrasound scanning

    (repeated if necessary), and complemented with EUS. Othertests may be needed to rule out peptic ulcer disease, subtlechronic pancreatitis, fatty liver disease, or musculoskeletalsyndromes. Esophageal manometry, gastric emptying tests,and transit studies may be required if symptoms suggestalternative dysfunctional syndromes. Further managementdepends on the level of clinical suspicion. The diagnosis ofFGBD may be made by exclusion if the pains are typical and

  • 1422 Cotton et al Gastroenterology Vol. 150, No. 6



    severe. A key issue is whether current methods for assess-ing GB muscular function are useful.

    Assessment of Gallbladder EmptyingCCK-CS is a popular diagnostic test, but its value is

    controversial. The test involves the intravenous adminis-tration of technetium 99m (Tc 99m)labeled hepatobiliaryiminodiacetic acid analogs. These compounds are readilyexcreted into the biliary tract, and are concentrated in theGB. The net activity-time curve for the GB is derived fromserial observations, and GB emptying is expressed as theGBEF, which is the percentage change of net GB counts.12

    An interdisciplinary panel proposed a standardized testand emphasized that proper patient selection is a criticalstep when considering whether to perform CCK-CS, becausedelayed emptying is seen in many other conditions,including asymptomatic individuals and patients with otherfunctional gastrointestinal disorders. The injection of CCKcan cause biliary-like pain, but using this observation todetermine patient-care decisions was discouraged by thepanel, because CCK also increases bowel motility, which cancause symptoms. In some countries, CCK preparations havenot been approved for human use.

    Other imaging methods. GB emptying can beassessed with ultrasound scanning after CCK or fatty mealstimulation, but these methods have not become popular.Attempts are being made to study emptying patterns duringmagnetic resonance cholangiopancreatography (MRCP)13

    and computed tomography (CT) scanning14 with resultsthat appear to mimic those of cholescintigraphy.

    Treatment of Functional Gallbladder DisorderSymptoms suggestive of FGBD often resolve spontane-

    ously,3 so that early intervention is unwarranted. Patientsmay respond to reassurance and medical treatments such asantispasmodics, neuromodulators, or ursodeoxycholic acid,

    although their value has not been evaluated formally. Cho-lecystectomy is considered when these methods fail, andsymptoms are severe. The reported results of surgery varywidely.2,3,15 Many claim benefit in >80% of patients, butmost studies are of poor quality with several potentialbiases; none have limited intervention to patients withnegative EUS exams. There has been only one small ran-domized trial, favoring cholecystectomy.16 Several author-ities have called for more definitive studies.3,17

    The predictive value of the CCK-CS