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Review

Gallstones: an intestinal disease?

During the first half of this century, cholelithiasis was

regarded as a disease of the gall bladder, with inflammationof the wall as the primary defect and exfoliated cells as thesource of biliary cholesterol.1 2 During the 1960s, Smalland Rapo elucidated the physicalchemical basis of biliarycholesterol supersaturation and demonstrated that exces-sive hepatic cholesterol secretion is the underlying defect.3

Cholesterol gallstones were then considered to be the con-sequence of a metabolic defect of the liver. The importanceof the gall bladder during gallstone formation wasresurrected during the 1980s, when impaired gall bladderemptying was identified as a factor contributing togallstone formation.4 5 During the past 10 years, a thirdorgan has been proposed as an important player in gallsto-ne pathogenesisthe intestine. Several recent observationsindicate slow intestinal transit in gallstone patients andanimal models. Impaired intestinal transit might promotegallstone formation by increasing the amounts of thehydrophobic bile salt deoxycholate or by other mecha-nisms. In this review, we shall evaluate critically the prosand cons of the intestinal hypothesis.

Cholesterol supersaturation and crystal formationCholesterol is a relatively insoluble amphiphile. Its solubil-ity in water is only 20 109 M, but in gall bladder bile,20 103 M of the sterol can be kept in solution.6 Thismillionfold increase in solubility is explained by incorpora-tion of cholesterol into micelles, together with bile salts andphospholipids (mainly phosphatidylcholine). Whereascholesterol is soluble only to a limited extent in micellesthat contain exclusively bile salts (simple micelles),addition of phosphatidylcholine leads to strongly enhanced

solubility in mixed micelles, provided that this phos-pholipid contains unsaturated acyl chains at the sn-2position.7 Supersaturation occurs when either too muchcholesterol or not enough bile salts and phosphatidylcho-line are secreted to allow complete micellar solubilisationof all cholesterol in bile. Current thought is that increasedbiliary cholesterol secretion rather than decreased bile saltor phospholipid secretion is the primary cause of biliarycholesterol supersaturation.8 Excessive cholesterol may besolubilised in vesicles (spherical bilayers of cholesterol andphospholipids, without bile salts). As these vesicles areoften cholesterol-rich, they maypossibly after aggrega-tion and fusionnucleate cholesterol crystals, an essentialstep in gallstone formation.9 10 A large number of proteinsare secreted in bile, among them apolipoproteins A1 and

A2, anionic polypeptide fraction, aminopeptidase N,

1acid glycoprotein, mucin, haptoglobin, immune globulins,phospholipases A2 and C, and others. Based on in vitrostudies, several of these proteins may either promote orinhibit crystallisation by stabilising or destabilisingcholesterol-rich vesicles.

Postprandial gall bladder motilityIngestion of a meal induces considerable gall bladderemptying, up to 7080% of fasting gall bladder volume, byreleasing the hormone cholecystokinin (CCK) from theduodenal wall. Apart from biliary cholesterol supersatura-tion and proteins, gall bladder motility may also influencegallstone formation. The basic concept is relatively simple:

impaired gall bladder emptying prolongs residence of bile in

the gall bladder, thus allowing more time for nucleation ofcholesterol crystals from supersaturated bile. Furthermore,in the case of adequate gall bladder emptying, cholesterolcrystals that have nucleated are ejected to the duodenum,whereas in the case of impaired gall bladder emptying, thesecrystals aggregate into macroscopic gallstones. Indeed, stud-ies in patients with gallstones by either scintigraphic orultrasonographic methods have identified a subgroup withimpaired emptying, as defined by a low percentage decreasein fasting volumes or low amounts of ejected bile after con-sumption of a meal.4 Even in patients with normal gall blad-der emptying according to these criteria, there are oftenincreased fasting and residual gall bladder volumes, despitenormal amounts of bile ejected after feeding.11 12 Tradition-ally, it has been assumed that after a meal, the gall bladderempties in a steady, progressive fashion and that gall bladderrefill occurs only in the fasting state, between meals. Thisassumption has been challenged by studies using combinedduodenal perfusion and scintigraphy13 or minute by minuteultrasound14: there seems to be very frequent, short periodsof gall bladder emtying and refilling (bellow concept), thebalance between them determining whether net emptyingsuch as in the immediate postprandial periodor net refill-ing occurs. One should realise that, strictly speaking,ultrasound measures only gall bladder volumes (which areinfluenced by refilling), and HIDA scintigraphy measuresthe reduction in total gall bladder isotope counts (which areindependent of refilling). Jazrawi and colleagues15 recentlyintroduced a method of combined scintigraphy andultrasound that enables simultaneous, accurate quantitationof gall bladder emptying and refilling, as well as bile turno-

ver. Interestingly, postprandial gall bladder emptying, refill-ing and bile turnover were all strongly depressed in patientswith gallstones, thus suggesting a reduced postprandialwashout eVect. Nevertheless, one may argue that abnormalgall bladder motility in these patients could be secondary tothe presence of stones or supersaturated bile in the gall blad-der, with no relevance for gallstone formation. Indeed, stud-ies in gallstone forming animal models have shown that, afterits absorption by the gall bladder wall from supersaturatedbile, excess cholesterol is incorporated within the sarcolem-nal plasma membrane of the gall bladder muscle cell, withdecreased membrane fluidity, impaired contractility andimpaired relaxation as a result.1618 Although impaired motil-ity could be in many cases secondary to biliary cholesterolsupersaturation, it may still facilitate the process of gallstoneformation: in the prairie dog model19 and in humans,20

impaired gall bladder motility occurs in the earliest stage ofgallstone formation, before stones have formed. Gall bladdermotility is also often impaired in many high risk situations forgallstone formation, such as pregnancy, obesity, diabetesmellitus, treatment with the somatostatin analogue octre-otide, very low calory diets, and total parenteral nutrition.Prospective studies indicate that impaired gall bladdermotility is also an independent risk factor for gallstonerecurrence after extracorporeal shockwave lithotripsy.21

Daily CCK injection during total parenteral nutrition22 or

Abbreviations used in this paper: CCK, cholecystokinin; MMC,

migrating motor complex.

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inclusion of small amounts of fat in the diet during rapidweight loss23 restore normal gall bladder motility and avoidthe risk of gallstone formation. All these data suggest a role

for gall bladder motility in gallstone formation.

The intestine: its relation to bile composition and gallbladder motility in the fasting (interdigestive) stateRecent data indicate that, along with the liver and the gallbladder, the intestine might also be involved in gallstoneformation. The gall bladder and the small intestine deter-mine enterohepatic cycling of bile salts and their fluxthrough the liver. In patients with gallstones, both smallintestinal24 and whole gut25 transit times are prolonged.What explanations could be oVered for the associationbetween prolonged intestinal transit and gallstone disease?One should remember one potential caveat: gallstones arerather frequent in the western world and the symptomsoften attributed to them, such as right upper quadrant

painwith or without radiation to the backor nausea,are not specific to gallstones.26 These symptoms can also becaused by constipation as they often disappear uponchanges in diet or pharmacological intervention. Aspecificabdominal symptoms may have led to ultrasonographicdetection of gallstones and clinicians with special interestin gallstone research may have measured intestinal transitand included these patients in their case-control studies.Nevertheless, one study explicitly states that patients wereunaware of the presence of stones.25 One could alsohypothesise that impaired intestinal motility is somehowcausally related to gallstone formation. Indeed, the hydro-phobic bile salt deoxycholate could be the link betweenimpaired intestinal motility and lithogenic bile. The mainbile salts in humans are cholate and chenodeoxycholate,

both primary bile salts synthesised from cholesterol inthe liver, and the secondary bile salt deoxycholateformed in the distal small intestine and colon by bacterial7-dehydroxylation of cholate. Deoxycholate is partlyabsorbed from the intestinal lumen and joins the enterohe-patic circulation of bile salts after taurine or glycine conju-gation in the liver. Prolonged intestinal transit timeprobably enhances formation of deoxycholate by increas-ing the intestinal residence time of bile salts, whereasdecreasing intestinal transit time may have the oppositeeVect. As a result amounts of deoxycholate vary consider-ably in humans, between 10 and 30% of the total bile saltpool. Preliminary data from Dowling and coworkers27 haverevealed that patients with gallstones have increased

amounts of Gram positive anaerobic bacteria and in-creased 7-dehydroxylating activity in their caecumcompared with controls. In these patients, slowness ofcolonic transit correlates with increased caecal pH andwater solubility of deoxycholate (factors promoting intesti-nal absorption of the bile salt). What eVects do increasedamounts of biliary deoxycholate in bile have on lithogenic-ity? Several studies in patients with gallstones have found apositive correlation between the amount of biliarydeoxycholate on the one hand and the cholesterol

saturation index24 28 or the speed of cholesterolcrystallisation28 on the other. In acromegalics, octreotidetreatment induces a similar combination of increasedintestinal transit times, more biliary deoxycholate, in-creased biliary cholesterol saturation index and fastcrystallisation.29 30 In contrast, treatment with ampicillinleads to decreased faecal 7-dehydroxylation activity,decreased amounts of biliary deoxycholate and a lower bil-iary cholesterol saturation index.31 In the ground squirrel32

and in the C57L inbred mouse,33 a cholesterol-rich dietinduces a significant increase in the proportion of biliarydeoxycholate, cholesterol supersaturation and gallstoneformation. Furthermore, in the ground squirrel model,small intestinal transit is prolonged.32 Thus, data frompatients with gallstones and acromegalics on octreotide as

well as animal models suggest an association between slowintestinal transit, high deoxycholate, cholesterol supersatu-ration and gallstone formation. One should realise,however, that this association is not universal: in humanson oral contraceptives (another risk factor for gallstoneformation), cholesterol supersaturation and slow intestinaltransit are associated with a decreased rather thanincreased deoxycholic acid pool size.34 Furthermore, inboth the ground squirrel and the C57L inbred mousemodels on lithogenic diets, there is an increased pro-portion, not only of biliary deoxycholate, but also of theprimary bile salt chenodeoxycholate. This might beexplained by negative feedback suppression through thehydrophobic deoxycholate on hepatic cholesterol 7-hydroxylase (the rate controlling enzyme in the classicpathway of bile salt synthesis) and a higher contribution to

bile salt synthesis of the alternative or acidic pathwaythrough the mitochondrial enzyme sterol 27-hydroxylaseas the alternative pathway has a preference for chenodeoxy-cholate over cholate synthesis.35 36

Increased deoxycholate could promote lithogenic bileand gallstone formation through several mechanisms.Firstly, deoxycholate itself can slow down intestinaltransit,37 thereby allowing more time for intestinalcholesterol absorption and exerting a positive feedback onits own formation. The mechanism for this eVect is notentirely clear: although in in vitro studies, bile salts seem toexert a depressant eVect on intestinal muscle contractility,38

increased maximal contractile responses of intestinalcircular and longitudinal smooth muscle strips on bethan-echol stimulation have been reported in ground squirrels

on a lithogenic diet, associated with slow small intestinaltransit and biliary deoxycholate enrichment.32 Moredeoxycholate could theoretically also increase intestinalcholesterol absorption by means of enhanced micellarsolubilisation of the sterol. This eVect, however, is probablymore relevant in animal models with rather hydrophilicendogenous bile salts32 33 than in humans with a relativelyhydrophobic endogenous bile salt pool. Secondly, deoxy-cholate could enhance biliary cholesterol secretion by aneVect on the hepatocytic canalicular membrane. The outerleaflet of the membrane contains large amounts of choles-terol and the phospholipid sphingomyelin (associated inlaterally separated domains), which confers resistance tothe detergent action of bile salts by decreasing membrane

Figure 1 The intestinal migrating motor complex occurs periodically(12 hour cycle) during the fasting state and is characterised by three

phases: contractile activity is absent during phase I; irregular activityoccurs during phase II; and there are intense, regular coordinatedcontractions during phase III. Significant periodic gall bladder contractionoccurs before phase III and is associated with a rise in plasma motilinconcentrations.

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fluidity. Particularly hydrophobic bile salts such asdeoxycholate can release cholesterol from the sphingomy-elin domains (most likely by decreasing the activationenergy necessary for desorption of the sterol from themembrane), thus allowing its secretion into bile.7 Thirdly,in vitro studies have revealed that deoxycholate enhancesbiliary cholesterol crystallisation by destabilising choleste-rol-rich vesicles.39 This eVect (paradoxical if one wouldonly consider the enhanced micellar cholesterol solubilisa-tion in deoxycholate-rich biles) can be nicely explained by

the elegant model studies performed by Wang and Carey40:deoxycholate leads to a rightward shift in the ternary(cholesterol-phospholipid-bile salt) phase diagram, withinherent faster cholesterol crystallisation.

Apart from the eVects on biliary deoxycholate another,possibly complementary, link between the intestine and gall-stone formation could be the relation between intestinal andgall bladder motility in the fasting (also called interdiges-tive) state. As fig 1 shows, significant periodic gall bladderemptying occurs during this period (2030% emptying inthe fasting state compared with 7080% emptying after ameal) at one to two hour intervals, associated with the cycleof the intestinal migrating motor complex (MMC) and witha rise in plasma motilin concentrations.41 42 The MMC, apattern of cyclic contractile activity displayed in the fasting

state by the upper intestinal tract, is characterised by threephases: during phase I, contractile activity is absent; irregu-lar activity occurs during phase II; and during phase III thereare intense, regular coordinated contractions. In healthypeople, significant gall bladder emptying and high plasmamotilin concentrations are observed before phase III.4244 Wefound that patients with gallstones have less frequent MMCcycles, absent interdigestive gall bladder emptying and analtered pattern of motilin release compared with controls. 45

A similarly prolonged MMC cycle has been found in theground squirrel model of gallstone formation.46 The fastingstate, namely the night, would seem to be the mostvulnerable period for gallstone formation. During thisperiod, biliary cholesterol saturation is highest as a result ofrelatively low bile salt secretion and relatively high choles-terol secretion. There is also a progressive concentration of

gall bladder bile during this period, which is partially coun-teracted by periodic interdigestive gall bladder contractionsin association with phase III of the MMC.47 Bile concentra-tion has important consequences: it leads to higher micellarcholesterol (and phospholipid) solubilisation by increasingthe micellar phase boundary.40 As phospholipids are muchmore easily solubilised in micelles than cholesterol, there is amuch larger shift of phospholipid than cholesterol from vesi-cles to micelles. The remaining vesicles should therefore beenriched in cholesterol and prone to nucleate cholesterolcrystals.48 49 According to this concept, the reduced fre-quency of phase III and absent interdigestive gall bladdercontractility, as found in our patients with gallstones, couldpromote bile concentration, crystallisation and gallstone for-mation. During the earliest stages of gallstone formation in

the prairie dog model there is also excessive concentration ofbile within the gall bladder50 and prevention of excessive bileconcentration with the aid of the drug amiloride preventsgallstone formation.51 Interestingly, cholesterol absorptionby the gall bladder wall seems to function as a protectivemechanism against cholesterol crystallisation under thesecircumstances, because it leads to a lower biliary cholesterolsaturation. Using the isolated pig gall bladder model,Corradini and colleagues52 have confirmed earlier reports53 54

that significant cholesterol absorption as well as some phos-pholipid absorption occurs from supersaturated biles. Incontrast, there is virtually no bile salt absorption. Thisdefence mechanism may be operating particularly in the caseof impaired gall bladder emptying.55 Based on indirect

evidence (comparison of protein concentrations in hepaticand associated gall bladder biles), Groen and coworkers56

have postulated a similar absorption of pronucleatingproteins by the gall bladder wall as an additional defence

mechanism against crystallisation.

SummaryCurrent evidence suggests that impaired intestinal motilitymay facilitate gallstone formation by influencing biliarydeoxycholate levels or by modulating interdigestive gallbladder motility (fig 2), although a primary intestinaldefect in gallstone pathogenesis has not yet beendemonstrated. In the cold war period, most interestingevents, from a political point of view, occurred at the bor-der between capitalist and communist systems, near theiron curtain. Similarly, the gall bladder and biliary tract canbe viewed as the border between liver and intestinal tract,where many interesting things occur with profound impacton both systems. Combined eVorts by researchers in thefield of hepatology and gastrointestinal motility shouldbrake down the Berlin wall of ignorance of one of the mostcommon diseases in the Western world.

K J VAN ERPECUMG P VAN BERGE-HENEGOUWEN

Department of Gastroenterology,

University Hospital Utrecht,

Postbox 85500,

3508GA Utrecht,

The Netherlands

Correspondence to: Dr van Erpecum.

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Figure 2 Potential mechanisms of cholest erol gallstone formation.

Frequency of intestinal migrating motor complex

Intestinal transit time

Deoxycholic acid pool size

Biliary cholesterol secretion

Bile concentration

Gall bladder hypomotilityDestabilisation of biliary vesicles

Cholesterol crystallisation

Gallstone formation

Are gallstones an intestinal disease? 437

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doi: 10.1136/gut.44.3.4351999 44: 435-438Gut

K J VAN ERPECUM and G P VAN BERGE-HENEGOUWENGallstones: an intestinal disease?

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