Gut, 1990,31,571-582 571 Biliary motility

P A Grace, G J Poston, R C N Williamson Gut: first published as 10.1136/gut.31.5.571 on 1 May 1990. Downloaded from

The delivery ofbile to the depends on the ampulla, which in turn is followed by another hepatic secretion of plus onward propulsion contraction. He likened this rhythmical contrac- through the . Biliary kinetics involve tion and relaxation of the sphincter segment to a series of complex interrelationships between systole and diastole, with filling of the ampula gall bladder, cystic duct, common , occurring during diastole and propulsion of bile and upper , into the duodenum during systole.6 Using low with control modulation by various neural and compliance manometric techniques, Toouli has hormonal agents. The application of modern shown that during fasting the human sphincter techniques to the study of biliary motility has ofOddi exhibits phasic contractions ofperistaltic allowed a composite physiological picture to type which propel bile into the duodenum and emerge. Moreover, alterations in biliary motility prevent reflux of duodenal contents into the bile are increasingly implicated in the aetiology of and pancreatic ducts.7 gall stones and postcholecystectomy symptoms. The present review examines recent develop- ments in the understanding of biliary motility Physiological motility and discusses the detailed events involved in delivering bile to the duodenum. BILE DUCT Bile flow is governed by a combination ofhepatic secretion, gall bladder contraction and sphincter Anatomical considerations of Oddi activity. The biliary tract is a low The anatomy of the biliary tree has been studied pressure system undergoing minimal pressure extensively in several species including man.'4 changes, whether during fasting or after feeding, The considerable species variation in biliary despite substantial changes in bile flow.38 The structure and function should prevent uncritical human liver secretes at least 1000 ml of bile per extrapolation from one species to another. Most day. Secretion decreases when the common duct vertebrates possess hepatic ducts, cystic duct, pressure rises above 10 cm of water, and with

gall bladder, , and sphincter of occlusion of the duct the pressure stabilises at http://gut.bmj.com/ Oddi, but for some reason the gall bladder is about 30 cm of water.9 Thus pressure is main- absent in certain species including horse, deer, tained at a relatively low level even in the rat, and pocket gopher. Among mammals there presence of outflow obstruction. Surgeons are three different patterns in the relationship recognise prolonged biliary obstruction by the between the termination of the bile and pan- presence of white bile, which indicates that creatic ducts: (1) the two ducts join to form a hepatic secretion has virtually ceased, residual

common channel; (2) the common bile duct and pigment has been reabsorbed and the duct is full on October 1, 2021 by guest. Protected copyright. pancreatic duct are distinct but share a common ofmucus derived from its own epithelium. entrance into the duodenum; (3) the biliary and pancreatic ducts open separately into the duo- denum.2 All three patterns can be seen in man, GALL BLADDER but type predominates. In man thickened muscle at the proximal and Pattern ofemptying distal margins of the sphincter of Oddi make up Recent data have shown that filling and empty- the 'sphincter choledochus' and the 'sphincter ing of the gall bladder are complex processes. ampullae' respectively. Boyden4 divided the The human gall bladder does not empty com- sphincter choledochus into a superior portion, pletely in response to food entering the duo- which encircles the distal common duct just denum, and there are frequent changes in its before it enters the duodenum, and an inferior absolute storage volume and rate of emptying.'0 portion surrounding the submucosal intra- Furthermore, partial emptying and refilling duodenal portion of the common duct. The occur synchronously with the migrating sphincter ampullae surrounds the ampullary myoelectric complex (MMC) of the intestine duct at the duodenal papilla. Cineradiographic during the interdigestive period. Thus, entry studies have shown the interaction of the various and exit of bile from a healthy gall bladder Department of Surgery, Royal Postgraduate human sphincters during the passage of bile into resemble more the gentle ebb and flow ofthe tide Medical School, the duodenum.5 Thus, a contraction begins in than myocardial systole and diastole. Hammersmith Hospital, the middle of the intramural portion of the duct Gall bladder tone reflects the inherent compli- Du Cane Road, London W12 ONN and propagates both upwards and downwards. ance of the smooth muscle and fibroelastic tissue The or retention the which in Correspondence to: Professor superior sphincter pushes within its wall, turn are modulated by R C N Williamson, bile in its segment up into the extramural bile autonomic and hormonal mechanisms. The Department of Surgery, Royal Postgraduate Medical School, duct, while the inferior or evacuation sphincter static compliance of the gall bladder, measured Hammersmith Hospital, and the sphincter ampullae propel the bile in by pressure volume relationships, takes 12-16 Du Cane Road, London W12 ONN. their segments into the duodenum.5 hours to adjust to the volume ofthe organ." Over Accepted for publication Hess6 has observed that each contraction ofthe shorter periods of two to four hours compliance 10 July 1989 human sphincter is followed by passive filling of remains relatively constant despite large fluctua- 572 Grace, Poston, Williamson

tions in volume." This property of slow tone ing." Thus CCK regulates the length oftime that adjustment would allow refilling during the bile stays in the gall bladder and remains subject period of increased bile secretion after gall to the concentrating capability of its mucosa. bladder contraction. Gall bladder emptying Cholecystokinin therefore regulates the bile acid/

starts as the stomach begins to empty, and gall cholesterol saturation index by gall bladder Gut: first published as 10.1136/gut.31.5.571 on 1 May 1990. Downloaded from bladder refilling starts when gastric emptying is volume change24 rather than by altering the nearly complete. 2 absorption or secretion of water and electrolytes Lanzini and colleagues'" have now defined the across the gall bladder mucosa.25 So, at low bile events occurring in bile flow between meals. acid secretion rates the bile secreted by the liver Most hepatic bile is diverted into the gall bladder becomes more saturated with cholesterol: bile not only during fasting but also after meals. This acid secretion rates are low when the enterohe- storage process alternates at short intervals with patic circulation of bile acids is sluggish, for ejection of bile from the gall bladder into the instance at night, as nocturnal fasting is associ- duodenum. Thus, the gall bladder behaves like ated with diminished CCK secretion and there- a set of bellows, and this property may be fore decreased gall bladder volume changes. important for thorough mixing ofits contents. Cholecystokinin acts directly on receptors in the muscle coat of the gall bladder.26 Optimal binding of '25I-CCK-33 occurs at pH 5 5 and The role ofcholecystokinin requires the presence of magnesium.26 Binding Sixty years ago Ivy and Oldberg'3 observed that of '25I-Bolton Hunter-CCK-8 to the CCK the intravenous injection of an extract of upper receptor requires the expenditure of cellular gastrointestinal mucosa caused contraction and energy.27 There is both regional and cellular evacuation of the gall bladder in cats and dogs. heterogeneity of CCK receptors throughout the Their classical cross-circulation studies showed gut. There is a 20-fold decrease in sensitivity to that acid injected into the duodenum of one the C-terminal residue of CCK-8 from gall animal caused gall bladder contraction in the bladder muscle to ileal circular muscle. Chole- parabiotic partner. They proposed the name cystokinin receptors on cholingeric neurones in 'cholecystokinin' for the hormone or active ileal muscle are between 80-300 times more principle that caused the gall bladder to contract. sensitive to CCK-8 than the adjacent muscle In 1968 Jorpes and Mutt isolated cholecysto- cells.28 Multiple exposures of guinea pig gall kinin (CCK) and described the chemical bladder to CCK-8 appear to increase the number sequence of its amino acids." Cholecystokinin is of CCK receptors (sensitisation), whereas in the released from the duodenum by luminal acid and guinea pig the opposite is seen (desensi- nutrients, in particular fat and amino acids.'5 tisation), associated with changes in the

The half life of CCK in the plasma of both man cholinergic receptors.29 These findings probably http://gut.bmj.com/ and dog is about 2 5 minutes.'5 The kidney is its relate to the primary neuronal nature of CCK major site of uptake from the systemic circula- receptors in the ileum and the combined neuronal tion.'5 The predominant forms of CCK (CCK-8, and muscular location of CCK receptors in the CCK-33, CCK-39, and CCK-58) are all released gall bladder. There is a wide range of binding by the upper gastrointestinal mucosa. In porta- capacity of CCK to its receptor between one gall caval transposition studies in dogs, Sakamoto bladder and another, but in general the binding

and colleagues showed that nearly all CCK-8 in affinity of 125I-D-Tyr-Gly+[(Nle)28 30 CCK-26- on October 1, 2021 by guest. Protected copyright. the portal circulation is metabolised on first 33] to gall bladder muscle has a Kd of around passage through the liver'6 and maintains a 1 nmol and 50% of this binding can be inhibited systemic activity; it is probably these forms of by 0 9 nmol CCK-8, 0-8 imol gastrin-17 and CCK that are primarily responsible for stimulat- 5 [imol CCK (gastrin)-4.30 The gall bladder ing gall bladder contraction and pancreatic muscle CCK receptor has been shown by covalent secretion. II cross linking studies to have a molecular weight The presence of pancreatic enzymes (particu- in the region 85 000-95 000.30 larly trypsin) inhibits CCK release from the The response of the gall bladder to CCK is duodenum.'"9 By contracting and stimulating calcium dependent. It is inhibited by the bile flow, the gall bladder also plays a role in the addition of calcium channel blocking agents.3' negative feedback suppression ofCCK release by Removal of calcium from the extracellular fluid the upper gut. In man and in dogs with bile in gall bladder strip preparations decreases the diversion, bile salts have been shown to inhibit contractile response to CCK by 80%.3' Hyper- the endogenous release of fat stimulated CCK calcaemia induced in normal volunteers by iv and neurotensin from the ileum.20 Thus, a self infusions of calcium chloride enhances CCK- regulating feedback loop has been established for stimulated gall bladder contraction in vivo.32 gall bladder emptying in response to duodenal Gall bladder contraction in response to CCK is food. also mediated by cholinergic vagal neurones. Infusions of CCK-8 cause the human gall Truncal vagotomy reduces the sensitivity of bladder to contract,2' and the degree ofchange in canine gall bladder to CCK (as measured by gall bladder volume is directly proportional to changes in intraluminal pressure).33 Truncal the concentration ofCCK detected in the plasma vagotomy may not alter the rate of gall bladder by radioimmunoassay.2' The volume and intra- emptying,34 motility being unchanged in the luminal pressure of the human gall bladder are early postoperative period in dogs.33 In man, inversely proportional to the circulating level of however, the postcontraction volume of the gall lipid-stimulated endogenous CCK.2223 It is now bladder is greater after complete vagotomy, generally believed that endogenous CCK is the suggesting a parasympathetic role in normal main driving force behind gall bladder empty- emptying.34 Biliaiy motility 573

Not only does vagal stimulation facilitate the gall bladder is supplied by three types of vagal response of the gall bladder to CCK, but it may nerve fibre: cholinergic, CCK-ergic and VIP- also regulate this response.36 Using ultrasound it ergic. Thus vagally regulated gall bladder tone can be shown that sham feeding stimulates gall and contraction is the net result of the interplay

bladder emptying in up to 50% of people, sug- of stimulatory fibres (mediated by acetylcholine Gut: first published as 10.1136/gut.31.5.571 on 1 May 1990. Downloaded from gesting a major role for vagal activity in gall and CCK) and inhibitory fibres (mediated by bladder motility. This response is eliminated by vasoactive intestinal polypeptide).55 Besides cholinergic blockade with atropine, again sug- diminishing the hepatic secretion of bile,57 gesting that the vagus can stimulate the gall somatostatin is a potent inhibitor of gall bladder bladder to contract.37 Cholecystokinin receptors emptying in man, whether meal-stimulated, on cholinergic postganglionic parasympathetic vagally-mediated or CCK-induced.58 Peptide YY neurones are much more important in mediating has recently been shown to potentiate gall the response ofthe gall bladder to CCK than they bladder relaxation and refilling after CCK- are in mediating the response of pancreatic acini induced contraction,59 and calcitonin gene to this hormone.38 Either hypersensitivity of the related peptide& and pancreastatin6' inhibit gall bladder to CCK or hyposensitivity of the CCK-induced gall bladder contraction in the sphincter of Oddi to CCK (resulting in the gall guinea pig. bladder contracting against a closed biliary system) may be the cause of acalculous in the small group of patients whose SPHINCTER OF ODDI symptoms can be reproduced by CCK infusion The role of the sphincter of Oddi is to regulate and who benefit from .39 bile flow into the duodenum, divert hepatic bile into the gall bladder and prevent reflux of duodenal contents into the biliary tree.3 The Other neurohumoral agents physiological sphincter of Oddi is characterised Other gastrointestinal peptides and neurotrans- by a high pressure zone located at the choledo- mitters have either cholecystokinetic actions choduodenal junction.6263 Physiological studies (direct and/or CCK potentiating) or cholecysto- of the sphincter of Oddi have centred on three static actions (direct and/or CCK inhibiting). main areas: (1) the relationship between Gastrin-17 belongs to the same family ofpeptides sphincter of Oddi activity and the activity of the as CCK. It causes gall bladder muscle contrac- surrounding duodenum; (2) the mechanism by tion in some species, though much less potently which the sphincter controls the flow of bile into than CCK4" and not at all in man.4' Secretin, the duodenum, and (3) the factors that control released from the upper gut by the presence of sphincter of Oddi function.

acid, abolishes the net water absorption from bile http://gut.bmj.com/ in the gall bladder.42 On its own secretin has no effect on gall bladder muscle,4243 but it has been Functional independence ofthe sphincter shown to potentiate the action ofCCK on the gall Early investigators" considered biliary flow to be bladder.44 Substance P is a direct stimulant of solely dependent on changes in duodenal tone gall bladder contraction in both dogs and and muscular activity. Others held that the rabbits,45 but its cholecystokinetic potency is sphincter of Oddi was functionally independent

only about one 600th that of CCK."6 Similarly ofthe duodenal musculature and was responsible on October 1, 2021 by guest. Protected copyright. motilin is weakly cholecystokinetic, but this for changes in biliary pressure.6547 More effect is limited to the quiescent period between recently, Mochinaga and colleagues68 have meals.47 The response of the gall bladder to shown that in the fasted state gastroduodenal neurotensin is species-specific. In dogs it causes motor activity plays a role in the regulation of gall bladder contraction with about one 50th the bile flow. Using a canine model they observed potency of CCK.48 In man, neurotensin causes that bile entered the duodenum only when the gall bladder relaxation in vivo, but this appears duodenal wall at the level of the choledocho- to be an indirect effect as neurotensin produces duodenal junction was not contracting or when no response in vitro.49 Histamine (H1) recep- the amplitude ofcontraction was small compared tor stimulation causes gall bladder muscle with the maximum amplitude of contraction contraction, whereas stimulation of type 2 during phase III, the active phase of the MMC. receptors (H2) causes gall bladder muscle They therefore suggested that when the duo- relaxation.50 denal wall contracts, it constricts the common Pancreatic polypeptide causes relaxation of bile duct and the cholechoduodenal junction to the gall bladder and decreased intraluminal impede bile flow. Others have showed a pyloro- pressure,5' which encourages refilling after con- cholecystic reflex69 and another a gastrosphincter traction.52 Infusions of CCK in man bring about of Oddi reflex,70 indicating a relationship release of pancreatic polypeptide, as measured between gastrointestinal and sphincter of Oddi by radioimmunoassay.53 Pancreatic polypeptide motility. remains raised for up to six hours after a meal, Both morphine and noradrenaline contract the suggesting that pancreatic polypeptide could sphincter but relax the duodenum.7' These find- play a role in the regulation of postprandial gall ings were confirmed by studying the effect of bladder filling.52 Vasoactive intestinal peptide adrenaline and noradrenaline on the isolated decreases resting gall bladder pressure in a dose- terminal bile duct.72 Ono and colleagues simul- dependent manner, eliminating spontaneous taneously recorded bile flow and electrical contractile activity.54 Vasoactive intestinal poly- activity from the sphincter and duodenum in peptide inhibits the contractile response of the humans. They found a negative correlation gall bladder to CCK in vivo" 55 and in vitro." The between bile flow and sphincter of Oddi elec- 574 Grace, Poston, Williamson

trical activity - that is, bile flowed into the promotion of bile flow through the sphincter of duodenum only in the absence of sphincter Oddi into the duodenum. electrical activity.73 Nevertheless, it seems reasonable to assume that the activity of the duodenal musculature can modify the rate ofbile Control mechanisms Gut: first published as 10.1136/gut.31.5.571 on 1 May 1990. Downloaded from delivery into the duodenum. The activity ofthe sphincter ofOddi is subject to many influences. In 1917 Meltzer proposed his 'Law of contrary innervation' whereby recipro- Bileflow into the duodenum cal contraction of the gall bladder and relaxation Several studies in animals and man show that the ofthe sphincter ofOddi was due to a fine nervous sphincter of Oddi has spontaneous phasic con- mechanism. Potter and Mann"' observed that tractions.7480 In man these phasic contractions perception of food caused a reduction in resist- occur at about four/minute and have a duration ance to bile flow, again indicating a neural of four to five seconds.75 Using a triple lumen influence on the sphincter. In 1926 Whitaker catheter with orifices spaced at 2 mm intervals demonstrated, however, that the denervated gall from the distal end for manometric measure- bladder can still contract in response to food.' ments, Toouli and his colleagues found that 60% Sandblom showed the hormonal action of of human phasic pressure waves propagate cholecystokinin on the sphincter of Oddi in towards the duodenum, 14% propagate in a 1935.87 Since then, several other hormones retrograde fashion towards the common bile including secretin,75 pentagastrin,88 serotonin,89 duct while 26% are simultaneous - that is, caerulein,88 glucagon75 and motilin9" have all propagate in both directions at once.8' Species been shown to affect the sphincteric activity. A differences in phasic wave direction make the role of neural mediation has reemerged from physiological purpose of this phenomenon recent work showing regulation of the sphincter unclear. In dogs the biliary sphincter may act as a by excitatory and inhibitory pathways." pump to expel bile into the duodenum,82 yet it Humoral and neural stimuli are in any case likely has also been observed that flow through the to be interlinked. common bile duct stops with each phasic con- traction of the sphincter.73798183 Moreover in cats, increased sphincter activity is associated (a) Hormonalfactors with increased resistance to flow through the The response of the sphincter of Oddi to CCK choledochoduodenal junction.7' varies according to species. In man CCK These apparent contradictions have now been decreases phasic wave activity and reduces base- resolved by Toouli's simultaneous analysis ofthe line pressure,75 while a similar response is found opossum sphincter, using cine-radiography, in primates76 and cats.77 In these species the http://gut.bmj.com/ transphincteric flow and electromyographic sphincter relaxes in response to CCK, thus facili- recordings.84 The main mechanism of common tating the passive flow of bile from the common bile duct emptying in the opossum is antegrade duct into the duodenum. The effect of CCK in contraction of the sphincter of Oddi. A wave of the rabbit,78 opossum79 and prairie dog,92 contraction begins at the junction ofthe bile duct however, is to increase the phasic wave activity and sphincter and strips the contents of the of the sphincter without affecting baseline sphincter segment into the duodenum (the pressure. In these species increased sphincter of on October 1, 2021 by guest. Protected copyright. systolic phase). During sphincter contraction no Oddi activity propels bile actively into the duo- flow occurs from the bile duct into the sphincter denum in response to CCK. segment. The sphincter then relaxes, and there is Until recently, the inhibitory actions of CCK passive flow of bile from the duct into the on the sphincter of Oddi were thought to be sphincter segment (the diastolic phase). A wave caused by a direct action of the hormone on the of contraction then begins again at the ductal/ sphincter muscle. New data now show that the sphincter junction, and the cycle repeats itself. effects of CCK on the sphincter of Oddi are The overall effect ofphasic contractions is there- mediated by non-adrenergic, non-cholinergic fore to promote flow from the common bile duct neurones that inhibit the feline sphincter of into the duodenum. Initially, increased contrac- Oddi. This effect masks a direct excitatory effect tions are accompanied by increased flow across of CCK on the sphincter muscle.77 In the the sphincter; but when the contractions exceed opossum, on the other hand, excitation of the a certain level, the diastolic interval is abolished sphincter of Oddi by CCK appears to be the completely and flow ceases. In the opossum, this result of a direct action of the hormone on the phenomenon occurs when the frequency of con- sphincter muscle.3 tractions exceeds eight/min.7 Other gastrointestical hormones and peptides A similar phenomenon has been described in can also affect the sphincter ofOddi. Caerulein is dogs.85 Intense phasic motor activity appears to a potent inhibitor of sphincter activity in a impede bile flow, whereas less intense activity number of species.889394 Gastrin, which shares an facilitates flow. Although species differences identical carboxyterminal pentapeptide with probably exist, the radiological studies of CCK and caerulein, also influences the chole- TorsoliSands5and Hes6 and the manometric observa- dochal sphincter.88 The potency ofthis hormone, tions of Toouli and colleagues8' indicate that the however, is considerably less than that ofCCK or human sphincter ofOddi also exhibits peristaltic caerulein. Agosti et al94 showed that human phasic contractions, which propel bile into the gastrin has only 10-40% ofthe activity ofCCK in duodenum and prevent reflex of duodenal con- relaxing the sphincter of Oddi in the anaesthe- tents into the bile and pancreatic ducts. Thus, tised guinea pig. Secretin reduces sphincter the purpose of phasic waves appears to be the resistance in the dog, probably indirectly by Biliary motility 575

potentiating the action of CCK. Glucagon also The biliary tract receives a parasympathetic decreases sphincter resistance in dogs88 and innervation from the vagus nerve.'06 Acetyl- man,63 and it is often used to relax the sphincter choline contracts both the gall bladder and the to facilitate cannulation during ERCP.3 sphincter of Oddi in the cat and calf.72106'07 Recently, motilin, serum concentrations of Cholinergic stimulation of the sphincter by Gut: first published as 10.1136/gut.31.5.571 on 1 May 1990. Downloaded from which fluctuate with phases of the interdigestive bethanecol increases the frequency of phasic MMC, has also been found to influence the contractions in the opossum.84 The function of sphincter of Oddi.3 In the dog85 and opossum95 the vagus nerve in sphincter of Oddi function phasic contractions exhibit cyclical variations in remains obscure,' 106 though recent work in the phase with the interdigestive MMC. Thus, the prairie dog has demonstrated increased resist- physiological role of motilin on the sphincter of ance to flow through the sphincter after truncal Oddi may be to regulate this cyclical activity vagotomy.80 Vagal stimulation studies have also during the interdigestive period. The actions failed to define clearly the role of the vagus in of motilin on the sphincter of Oddi may be biliary dynamics. Some investigators have mediated by an intramural excitatory pathway, reported sphincter contraction during vagal which appears to consist of opiate, serotoniner- stimulation,"0 but others could not detect any gic and cholinergic neurones.-* response to either central or peripheral stimula- The effects of pancreatic polypeptide, tion of the vagus."' peptide-YY, and neuropeptide-Y on biliary Behar and Biancani have suggested the motility are controversial. Both pancreatic poly- presence of non-cholinergic, non-adrenergic peptide and peptide-YY have been shown to neurones in the sphincter of Oddi.77 Studying enhance gall bladder filling in the prairie dog.9798 the feline sphincter of Oddi, they observed that Tatemoto and Mutt reported that peptide-YY CK-induced sphincter relaxation was not stimulates gall bladder contraction in vitro99 but antagonised by either adrenergic or cholinergic does not affect CCK-8-stimulated gall bladder blockade. Either CCK has a direct action on contraction in the anaesthetised guinea pig.1° sphincteric smooth muscle, therefore, or its Likewise, peptide-YY does not influence resting effects are mediated by a different neurotrans- gall bladder tension or CCK-stimulated gall mitter. In support of such a neurological bladder contraction in dogs;'0' we have shown pathway, administration of tetrodotoxin, which similar results in the prairie dog. 102 Nonetheless, blocks nerve transmission without affecting peptide-YY inhibits the increase in phasic con- smooth muscle, completely antagonised the tractions of the sphincter usually observed with effects of CCK on the sphincter.77 CCK-8. Thus, pancreatic polypeptide and peptide-YY may play a role in modulating biliary motility in the postprandial state by inhibiting http://gut.bmj.com/ bile flow into the duodenum and promoting gall (c) Pharmacologicalfactors bladder filling. Since neuropeptide-Y increases Morphine has long been known to increase sphincter of Oddi activity and gall bladder resistance to bile flow. Studies in a number of pressure in the prairie dog,'03 it could be a species71 82 have shown that the sphincter of Oddi neurotransmitter or neuromodulator regulating is very sensitive to opiates, responding with bile flow. marked contractions to low doses of morphine sulphate. In man small doses of morphine on October 1, 2021 by guest. Protected copyright. increase the rate of phasic contractions of the sphincter of Oddi;3 phasic wave amplitude and (b) Neuralfactors baseline pressure are also increased."2 Thus, Perception of food causes a reduction in the morphine is contraindicated in the management resistance to bile flow through the choledocho- ofbiliary pain. Pethidine also produces a marked duodenal junction," indicating a neural rise in biliary pressure but its effect is only half influence on the biliary sphincter. Recent that of morphine."3 Amyl nitrate consistently neurohistochemical studies have shown both relaxes the sphincter of Oddi across several adrenergic and cholinergic neurones within the species.83""'"' This inhibitory effect has been sphincter ofOddi ofthe cat and dog.104Persson"'5 used clinically to distinguish sphincter spasm suggests that the cat gall bladder and sphincter from stenosis. contain both adrenergic a-receptors (mediating Nifedipine, a calcium channel blocker, has contraction) and adrenergic ,6-receptors (mediat- also been shown to reduce baseline sphincter of ing relaxation). In the gall bladder ,3-receptors Oddi pressure as well as the frequency, ampli- predominate, while in the sphincter a- and ,B- tude and duration of phasic contractions."5 receptors are more evenly distributed. Relaxa- Intravenous butylscopolamine bromide (given tion of the sphincter in response to adrenergic iv) will decrease sphincter of Oddi motility stimulation, however (,-receptors), occurs only without affecting baseline pressure."6 Alcohol when the a-receptors have previously been administered either iv or into the duodenum blocked with phenoxybenzamine.'05 Although causes a moderate decrease in baseline pressure both receptor types exist in sphincter smooth without affecting sphincter motility."6 Recent muscle, mainly a-adrenoreceptors are activated endoscopic manometry in humans given penta- by sympathetic nerve stimulation. Thus, zocine has shown higher baseline pressures and adrenergic stimulation causes the sphincter of increased amplitude ofphasic contractions in the Oddi to contract and the gall bladder to relax. sphincter."' Fentanyl has also been associated This mechanism may be important during gall with sphincter spasm during peroperative bladder filling by promoting the entry ofbile into cholangiograaphy,"8 whereas diazepam is with- the gall bladder. out such effects.63 576 Grace, Poston, Williamson

Various anaesthetic agents influence sphincter Pathophysiology ofOddi function. Thus small iv doses ofbarbitu- rate increase flow through the sphincter."9 DYSMOTILITY AND GALL STONES Xylazine and ketamine affect biliary tract In 1856 Meckel von Helmsbach proposed that

motility in the prairie dog and should therefore mucus might form a nidus, but that stasis was Gut: first published as 10.1136/gut.31.5.571 on 1 May 1990. Downloaded from be avoided during physiological studies of the necessary for cholesterol to 'adhere' to this and sphincter.'20I2 Lastly, a recent study in dogs has create a gall stone." It has been argued that the shown inhibition of endogenous CCK release by presence ofestablished calculi affects neither the several different anaesthetic agents (with the physiology of biliary constituents (bile salts, exception of a-chlorolose), which may therefore cholesterol and phospholipids) nor the con- affect sphincter motility indirectly.'22 tractility of gall bladder muscle. 3' Whether alterations in gall bladder contractility play an aetiological role in gall stone formation is contro- versial. One survey has shown increased post- (d) Physicalfactors prandial emptying of the gall bladder in patients Temperature affects sphincter ofOddi activity in with cholesterol stones.'32 These authors sug- rabbits, cold being inhibitory and a rise to 40°C gested that such an increase in gall bladder being stimulatory.83 Increasing the blood emptying would be associated with a decreased pressure in dogs by infusing saline raises bile acid pool and in turn precipitate lithiasis. sphincter opening pressure, whereas hypoten- These patients also had increased gall bladder sion produced by haemorrhage diminishes sensitivity to CCK.33 Another group found opening pressure."' That sphincter activity is unchanged gall bladder sensitivity to CCK in influenced by the degree of gall bladder filling is vivo but altered contractility in response to CCK well established.749219 In the prairie dog, for in vitro; contractility increased in early disease example, distending the gall bladder increases but decreased in advanced disease.34 These sphincter activity and emptying it has the data'32-' are, however, at variance to the opposite effect, the so-called cholecystosphincter majority of published studies on the correlation ofOddi reflex.74 A relationship has recently been between altered gall bladder motility and gall shown between sphincter of Oddi activity and stone formation. the interdigestive or migrating myoelectric com- Many clinical and experimental studies con- plex.95123 Two groups of investigators have firm decreased gall bladder emptying in the shown in the conscious opossum that phasic presence of gall stones.'35142 In the prairie dog, contractions are synchronous with spike poten- prevention ofstasis by periodic administration of tials in the sphincter and that both exhibit CCK lowers the incidence of gall stones.35 cyclical changes that correlate with the MMC.95 123 Increased resistance to flow in the cystic duct http://gut.bmj.com/ Using a canine model, Mochinaga has demon- delays gall bladder emptying and predisposes to strated a relationship between gastroduodenal calculi.'43 Increased viscosity of gall bladder bile motor activity and bile flow.68 may result from hyperconcentration during delayed emptying.'"4 Calculous gall bladders have diminished sensitivity to prostaglandin stimulation of smooth muscle contraction,'45 but

(e) Intraluminal stimuli prostaglandins are not the prime mediators of on October 1, 2021 by guest. Protected copyright. Early investigators observed that introduction of gall bladder emptying. Patients with gall stones acid into the stomach increased resistance to bile have raised CCK concentration in their duodenal flow entering the duodenum in the anaesthetised mucosa compared with normal controls.'" This dog, whereas alkali achieved the reverse.'24 In may be because ofincreased synthesis ofCCK in patients with previous cholecystectomy installa- order to promote gall bladder emptying ifthe gall tion of dilute hydrochloric acid into the duo- bladder is less sensitive to CCK, or alternatively denum causes a transient increase in sphincter of it may be because of a failure to release CCK Oddi resistance, which can be blocked with which results in poor gall bladder emptying in atropine. 125 response to the presence of food and acid in the Fifty years ago, Best and Hicken'26 inferred duodenum. On balance, we favour the former from cholangiographic evidence that cream and hypothesis. During gall stone formation in the olive oil relax the human sphincter of Oddi, but prairie dog, changes in gall bladder motility Doubilet could not confirm this finding in precede changes in bile salt pool size.'47 Dysmo- patients after cholecystectomy.'2' A more exten- tility may reflect a diminished contractile sive investigation of cholecystectomy patients response to CCK'" rather than alterations in showed that an egg yolk meal caused relaxation membrane excitation, excitation-contraction but olive oil did not; protein also caused slight coupling or total content of contractile proteins relaxation ofthe sphincter, but carbohydrate had in gall bladder muscle. no effect."4 Recent work in the prairie dog has Thompson and colleagues'37 have described a shown that intraduodenal infusions of acidified group of gall stone patients whose gall bladders saline'27 and sodium oleate'28 decrease sphincter failed to contract with the normal endogenous of Oddi activity, whereas protein infusions release of CCK after a fat meal. They termed stimulate sphincter activity.'29 Exogenous CCK these patients 'non-contractors'. CCK-induced consistently increases sphincter of Oddi activity contraction of their gall bladder muscle strips in this species.91192 These conflicting data may be were correlated with the preoperative contrac- explained by evidence in rodents that CCK is not tility of the gall bladder in response to endo- released after ingestion of fats but is released by genous CCK. 'Non-contractors' were shown to protein.30 have fewer CCK receptors in gall bladder muscle Biliary motility 577

than other gall stone patients whose gall bladders and contractility to exogenous CCK owing to a contracted normally to endogenous CCK. In the decrease in gall bladder CCK receptors. 162 guinea pig too, experimental cholelithiasis is Although age lessens the sensitivity of gall associated with decreased biliary motility owing bladder muscle to CCK, therefore, there is a

to fewer CCK receptors. 149 compensatory increase in CCK release, which Gut: first published as 10.1136/gut.31.5.571 on 1 May 1990. Downloaded from After major abdominal operations reductions maintains near normal gall bladder emptying. in bowel motility, CCK release and vagal activity The mechanism that correlates the age could all lead to gall bladder hypotonicity and related decrease in gall gladder emptying to biliary stasis predisposing to gall stones.50 increased compensatory CCK release is probably Reduced motility of gall bladder and intestines the bile salt inhibition ofCCK release postulated alike may contribute to gall stone formation after by Gomez and colleagues.20 Decreased gall truncal vagotomy, when increased resistance at bladder emptying results in less bile salts reach- the sphincter of Oddi8" and gall bladder dilata- ing the duodenum and therefore greater CCK tion'5' may both be factors. Patients receiving release. In extreme youth the gall bladder prolonged total parenteral nutrition are also at response to CCK is different. Ultrasonography risk of rapid gall stone formation; bile stasis has been used to measure the contraction ofboth appears to be the major aetiological event.0' 152 maternal and near term fetal human gall bladders Interestingly, children on longterm total in response to a standard maternal meal. 163 parenteral nutrition seldom develop gall stones Maternal gall bladder size decreases, but fetal unless other aetiological factors are also present - gall bladder size is unchanged. It is not known if for example, necrotising or distal maternal CCK can cross the placenta. Indeed, ileal resection resulting in reduced bile salt pool whether any derivatives ofthe maternal meal can or biliary stasis.'"1'4 The frequency and severity reach CCK cells in the fetal duodenum in of acute , both calculous and sufficient quantities is unknown, likewise acalculous, in seriously ill patients after trauma nothing is known of the ontogeny of CCK or major surgery necessitate urgent ultrasono- physiology during embryonic development in graphy and prompt cholecystectomy if the diag- man. In guinea pigs the magnitude ofcontractile nosis is suspected. "I Daily administration of response of gall bladder strips to various CCK to patients on longterm total parenteral stimulants (including CCK) increases pro- nutrition might prevent this complication. 156 gressively from the preterm fetus to the mature One interpretation of the evidence that impli- adult. "64 These data indicate that cholinergic and cates altered biliary motility in the aetiology CCK receptors are present and functional before of gall stone formation is that gall bladder birth, but the contractile power of gall bladder activity must be maintained in a tight narrow muscle continues to develop after birth.

band between overactivity reducing the bile acid Certainly, in the guinea pig gall bladder CCK http://gut.bmj.com/ pool with consequent lithiasis,' '2-1' and under- receptors decline in number with advancing activity causing stasis and gall stone precipita- age. 162 tion.'35-156 Furthermore, as argued earlier, a A possible aetiological factor in the biliary reduction in the rate of turnover of the eftero- stasis ofageing is the presence ofduodenal juxta- hepatic circulation ofbile acids is associated with papillary diverticula.'65 The association between reduced hepatic bile acid secretion, so on balance such diverticula and common bile duct stones is

we support the view that decreased biliary well documented;'65 perhaps dysfunction of the on October 1, 2021 by guest. Protected copyright. motility rather than increased biliary motility is sphincter of Oddi allows reflux of duodenal the aetiological event in cholelithiasis. contents into the lower common bile duct."' We have shown that the rate of development of experimental gall stones in the guinea pig BILIARY MOTILITY AND AGEING correlates directly with age and can be prevented Boyden and Grantham investigated the effect of by administration of CCK to provoke biliary age on gall bladder emptying in 1926,'57 using emptying. 167 oral cholecystography after a standard 'Boyden meal' (five egg yolks well stirred in half a pint of cream). The rate of gall bladder emptying CHOLECYSTECTOMY AND THE SPHINCTER decreased sharply between childhood and adult- OF ODDI hood but remained constant thereafter. When Nearly half a million are per- cholecystograms were reviewed from subjects formed each year in the United States,'" yet very aged 60-83 years, a quarter of those without gall little is known about the effect of this operation stones had evidence of delayed emptying.'58 In on the sphincter of Oddi. Ruggero Oddi was the support, both fasting and corn oil-stimulated first to observe that cholecystectomy resulted in concentrations of CCK in plasma are higher in marked dilatation of the common bile duct in older than younger healthy volunteers, though dogs:'69 'La bile se recueille dans la vesicule ultrasonic estimates of gall bladder volume were biliare ou dans les conduits biliares tres dilatables similar.'59 The CCK content of upper small des animaux qui manquent de cette derniere'. bowel mucosa increases progressively with age in These findings were confirmed by Judd and normal human subjects'46 and guinea pigs,'60 Mann, who also found increased luminal although it is not known if this is the result of pressure in the bile duct.'70 Subsequent work has increased synthesis or decreased release ofCCK. also shown that the common bile duct dilates in The in vitro response ofrabbit gall bladder strips animals after cholecystectomy,'7' but autopsy to CCK diminishes between six months and four and radiological studies in man do not confirm a years of age,'6' and in the guinea pig in vivo there clear cut effect.'72173 Patients with choledocho- is an age related loss of gall bladder sensitivity lithiasis have recently been shown to have greater 578 Grace, Poston, Williamson

TABLE Sphincter ofOddi dysfunction Structural Functional Biliary I Biliary II Biliary III

Presentation 1 Biliary type pain 1 Biliary type pain 1 Biliary type pain only Gut: first published as 10.1136/gut.31.5.571 on 1 May 1990. Downloaded from and 2 Abnormal LFTs on 2 occasions 2 Abnormal LFTs on 2 occasions or 3 Delayed drainage of contrast 3 Delayed drainage on contrast on ERCP >45 min on ERCP >45 min or 4 Dilated CBD > 12 mm 4 Dilated CBD > 12 mm Manometry Optional Necessary for diagnosis Mandatory 1 Elevated SO basal pressure 1 SO hypertonicity or spasm 2 Reduction ofpressure or SO 2 Paradoxical response phasic wave amplitude with to CCK-OP CCK-OP or amylnitrite 3 SO tachyoddia 4 Altered SO phasic wave sequence Treatment Operative sphincteroplasty Endoscopic sphincterotomy LFTs=liver function tests; ERCP=endoscopic retrograde cholangiopancreatography; CBD=common bile duct; SO=sphincter of Oddi; CCK-OP=cholecystokinin octapeptide

common duct diameters than normal volunteers, segment.'78 This is a structural problem resulting and it appears that after cholecystectomy further from fibrosis of the sphincter. Aetiological dilatation of these ducts occurs in the absence of factors include injury by impacted stones or symptoms. '74 operative instrumentation, infected bile and Recent studies have shown the presence of a .'781-81 cholecystosphincteric reflex suggesting that To distinguish organic stenosis from biliary sphincter activity is mediated, at least in part, , Hogan and Geenen have proposed a by the degree of gall bladder distension.74'9 classification based on clinical, laboratory and Furthermore, in dogs CCK release is increased radiological findings which recognises three in response to fat stimulation after cholecystec- groups of patients'78 (Table): group I patients tomy.'75 This finding could reflect loss of bile salt have biliary pain, abnormal liver function tests inhibition of CCK release,28 as bile salt flow will on two or more occasions, delayed drainage of no longer surge when the gall bladder empties ERCP contrast beyond 45 minutes and a dilated http://gut.bmj.com/ after a meal. In prairie dogs the sphincter ofOddi common bile duct >12 mm in diameter. These behaves differently after cholecystectomy, with patients are likely to have a structural problem, altered responses to CCK and intraduodenal ie papillary stenosis, and manometry is optional. fat. 128 Group II patients have biliary pain but only one or two of the other criteria. As their lesion could be structural or functional, sphincter of Oddi

'POST CHOLECYSTECTOMY SYNDROME manometry helps to separate the two. Raised on October 1, 2021 by guest. Protected copyright. Although cholecystectomy is a safe and effective baseline pressures which decrease with iv CCK- operation, 20% of patients develop either new OP (20 ng/kg) or inhalation of amyl nitrite gastrointestinal symptoms or recurrence of the indicate a functional rather than a structural symptoms for which the operation was recom- abnormality, but in either case endoscopic mended.'76 This unfortunate outcome has been sphincterotomy may be beneficial.78 Group referred to as 'the post cholecystectomy syn- III patients present only with biliary pain drome', but it is unlikely that there is such a and probably have 'true' sphincter of Oddi specific entity. Many non-biliary conditions can dyskinesia; manometry is essential to define the mimic the symptoms of biliary tract disease and abnormality, and again endoscopic sphinctero- should be considered in the differential diagnosis tomy may be helpful.78 of such patients. These include pancreatitis, Fibrosis and inflammation of the papilla of peptic ulcer, reflux oesophagitis, right sided Vater have often been documented at operation colonic and the irritable bowel and may be associated with biliary tract disease syndrome.'77 Common duct stones, retained gall and/or recurrent . 182-185 bladder and traumatic stricture of the bile duct Symptoms do not, however, necessarily coincide are obvious potential explanations for post with the severity of histological change.'83 In a cholecystectomy problems. Although a long prospective study of 28 patients with post- cystic duct remnant is sometimes implicated,'76 cholecystectomy pain, Moody found an the evidence is unconvincing unless stones are abnormal papilla in 82%. 184 Anterior sphinctero- contained in the stump.'" Some patients with plasty and transampullary septectomy gave long- post cholecystectomy symptoms may have motor term relief of pain or symptomatic improvement dysfunction of the sphincter, including papillary in 76% of patients,'86 and we too have found this stenosis and biliary dyskinesia. operation beneficial.'85 Nonetheless, the exten- sive amount of collagen that is normally present within the papilla makes the histological diagno- PAPILLARY STENOSIS sis of fibrosis difficult,'82 so that a clear cut Papillary stenosis has been defined as a narrow- differentiation from biliary dyskinesia is not ing of all or part of the sphincter of Oddi always possible. Biliary motility 579

BILIARY DYSKINESIA metry have generated important new data. Biliary dyskinesia is defined as a primary dis- Although primarily mediated through CCK, gall order of the tonic or phasic motor activity of the bladder emptying and refilling are the net result sphincter of Oddi.'78 Long suspected as a source of a whole symphony of stimulatory and inhibi-

of after cholecystectomy, tory agents. Opening of the sphincter of Oddi, Gut: first published as 10.1136/gut.31.5.571 on 1 May 1990. Downloaded from sphincter spasm was described by Parvel in 1932 once thought to be a simple passive relaxation, is and termed biliary dyskinesia by Ivy and a highly synchronised, dynamic and propulsive Sandblom two years later.'87 In early radio- event. What is apparent from this review is that graphic and manometric studies ofeight patients there is potential for many other hormonal, with T-tubes, McGowan and colleagues neurological, and pharmacological mechanisms observed that morphine provoked a rapid rise in in the regulation of biliary motility. Further- intrabiliary pressure associated (in one patient) more, recognition of pathophysiological with severe epigastric pain similar to that experi- mechanisms will lead to accurate diagnosis and enced before cholecystectomy.'88 Furthermore, treatment of symptomatic patients. More unprovoked episodes ofpain were also associated importantly, virtually nothing is understood of with a marked rise in intrabiliary pressure. the molecular events that occur beyond the cell These classical studies indicated a pivotal role for membrane within biliary smooth muscle once the sphincter of Oddi in raising intrabiliary the events of gall bladder emptying have been pressure and causing abdominal pain. The hypo- provoked, and further research is required in thesis was soon supported by Colp's observation this area. that sphincterotomy could often relieve post Now that the treatment of biliary disorders is cholecystectomy pain'89 and by Dahl-Iverson's no longer the private estate of the surgeon, it discovery that with an intact sphincter patients behoves all who endeavour to treat patients with with presumed biliary dyskinesia could still gall stones, acalculous cholecystitis, biliary experience episodic pain even with a T-tube to dyskinesia and papillary stenosis to develop a provide dependent drainage." better understanding of these complex physio- Attempts to identify biliary dyskinesia by logical processes. pharmacological provocation of pain or pan- creatic enzyme changes have had varying success. Nardi and Acosta introduced the 1 Boyden EA. The comparative anatomy of the sphincter of morphine-neostigmine provocation test in which Oddi in mammals, with special reference to the choledo- papillary contraction is stimulated by morphine choduodenal junction in man. In: Taylor W, ed. The biliary system, a symposium of the NATO advanced study institute. and pancreatic secretion by neostigmine.'9' In Oxford: Blackwell Scientific Publications, 1965: 15-40. one series 16 of 23 patients with abdominal pain 2 Mann FC, Foster JP, Brimhall SD. The relation of the common bile duct to the pancreatic duct in common and a positive Nardi test had moderate to marked domestic and laboratory animals. J Lab Clin Med 1920; 5: http://gut.bmj.com/ signs of papillary stenosis on endoscopic evalua- 203-6. 3 Hogan WJ, Dodds WJ, Geenen JE. The biliary tract. In: tion.'92 Other investigators have found this test Christensen J, Wingate DL, eds. A guide to gastrointestinal much less specific, either failing to confirm any motility. London: Wright PSG, 1983: 157-97. 4 Boyden EA. The anatomy of the choledochoduodenal correlation with papillary stenosis at operation'93 junction in man. Surgery 1957; 104: 641-52. or finding positive tests in 60% of healthy 5 Torsoli A, Ramorino ML, Palagi L, et al. Observations roentgen-cinematographiques et electromanometriques controls and patients with irritable bowel syn- sur la motilite des voies biliares. Sem Hop Paris 1961; 37:

drome.'" An operative sphincteroplasty of the 790-802. on October 1, 2021 by guest. Protected copyright. 6 Hess W. Manometry and radiography in the biliary system pancreatic duct, however, renders Nardi- during surgery. In: Demling L, Classen M, eds. Endoscopic positive patients Nardi-negative.'85 sphincterotomy of the papilla of Vater. Proc of the Inter- national Workshop ofthe World Congress ofGastroenterology. The development oftransendoscopic papillary Munich: Georg Thieme, 1976: 19-23. manometry has provided a method for direct 7 Toouli J. Sphincter of Oddi motility. Br J Surg 1984; 71: 251-6. assessment of sphincter of Oddi motility.75 A 8 Kern MK, Nakaya M, Dodds WJ, Layman RD, Hogan WJ. spectrum of manometric abnormalities has been Pressure kinetics ofthe biliary tract in conscious opossums [Abstract]. 1986; 91: 1058. identified in patients with post-cholecystectomy 9 Hallenbeck GA. Biliary and pancreatic pressures. In: The pain by means of this technique.'95 High fre- Handbook of Physiology, section 6, The Alimentary Canal Vol 2. Secretion Code CD: ed. American Physiological quency of phasic contractions ('tachyoddia'), Society. Washington DC: 1968: 1007-25. raising of baseline pressure, paradoxical 10 Lanzini A, Jazrawi RP, Northfield TC. Simultaneous quantitative measurements ofabsoluter storage response of the sphincter to CCK and altered and emptying during fasting and eating in humans. direction of phasic waves have all been des- Gastroenterology 1987; 92: 852-61. 11 LaMorte WW, Schoetz DJ Jr, Birkett DH, Williams LF Jr. cribed.8" 95 The therapeutic implications of these The role of the gallbladder in the pathogenesis of changes have yet to be determined, but pre- cholesterol . Gastroenterology 1979; 77: 580-92. 12 Lawson M, Everson GT, Klingensmith W, Kern F Jr. Co- liminary studies suggest that some patients with ordination of gastric and gallbladder emptying after sphincter of Oddi dysfunction may benefit from ingestion ofa regular meal. Gastoenterology 1983: 866-70. 13 Ivy AC, Oldberg E. A hormone mechanism for gall-bladder endoscopic sphincterotomy. 'I If pancreatic duct contraction and evaculation. Am J Physiol 1928; 86: 599- obstruction contributes to the pain, however, an 613. 14 Mutt V, Jorpes JE. Structure of porcine cholecystokinin- operative double sphincteroplasty seems likely pancreozymin. 1. Cleavage with thrombin and with to give a better result.'85. trypsin. EurJ Biochem 1968; 6: 156-62. 15 Thompson JC, Fender HR, Ramus NI, Villar HV, Rayford PL. Cholecystokinin metabolism in man and dogs. Ann Surg 1975; 182:496-504. 16 Sakamoto T, Fujimura M, Newman J, Zhu X-G, Greeley Conclusion GH Jr, Thompson JC. Comparison of hepatic elimination Before the advent of modern research tech- of different forms of cholecystokinin in dogs. Bioassay and radioimmuno assay comparison of cholecystokinin- niques, knowledge of the physiology and patho- -sulfate and -33-sulfate. J Clin Invest 1985* 75: 280S5. physiology of biliary motility was rudimentary. 17 Eysselein VE, Eberlein GA, Hesse WH, Singer MV, Goebell H, Reeve JR Jr. Cholecystokinin-58 is the major form of Now hormone and receptor assay, ultrasono- circulating cholecystokinin in canine blood. J Biol Chemn graphy, cholecystography and endoscopic mano- 1987; 262: 214-7. 580 Grace, Poston, Williamson

18 Owyang C, May D, Louie DS. Trypsin suppression of 48 Fujimura M, Sakamoto T, Khalil T, Greeley GH Jr, pancreatic enzyme secretion. Differential effect on Townsend CM Jr, Thompson JC. Physiologic role of cholecystokinin release and the enteropancreatic reflex. neurotensin in gallbladder contraction in the dog. Surg Gastroenterology 1986; 91: 637-43. Forum 1984; 35: 192-4. 19 Folsch UR, Cantor P, Wilms HM, Schafmayer A, Becker 49 Walker JP, Khalil T, Wiener I, Fagan CJ, Townsend CM Jr, HD, Creutzfeldt W. Role of cholecystokinin in the Greeley JH Jr, Thompson JC. The role of neurotensin in

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