Progress report - Gut · Gut, 1983, 24, 579-593 Progress report Gall-bladderwaterandelectrolyte transportandits regulation Diemerbroek' in 1672 appreciated that bile entered the gall

Gut, 1983, 24, 579-593

Progress report

Gall-bladder water and electrolytetransport and its regulation

Diemerbroek' in 1672 appreciated that bile entered the gall bladder to'acquire greater strength and digestive power'. A study by Rous andMcMaster2 in 1921 and later work by Ravdin and his coworkers3 4provided direct experimental support for the notion that the gall bladderconcentrates hepatic bile by selective reabsorption of bile constituents.These early studies have been reviewed in detail by Ivy.5 The nature ofwater and electrolyte absorption by gall-bladder mucosa has beenextensively studied by Diamond and his colleagues whose work hasprovided an important basis for understanding of transport by this andother more complex epithelia.68 Subsequent studies using isotope andelectrophysiological techniques which have sought to define the ionic basisfor salt and water transport by gall bladder are the subject of severalreviews.9-11 Recent experiments on the effects of gastrointestinalhormones and other secretagogues on gall-bladder transport haveestablished that the gall bladder, like the intestine, is able to reverse thedirection of its transport from a net absorption to a net secretion.'2 Thefinding that feeding in the conscious monkey can abolish gall-bladder fluidabsorption and reverse it to a net secretion provides for the first time directevidence that the rate and direction of fluid absorption by the gall-bladdermucosa are subject to physiological regulation during digestion. 13

In this report we review recent studies contributing to the understandingof fluid and electrolyte transport by the gall bladder with particularreference to physiological control mechanisms and pathological changeswhich modify it.

Transport mechanisms

SODIUM AND CHLORIDE TRANSPORTThe rate of transcellular sodium transport depends on the rate of sodiumentry across the luminal cell membrane and the active sodium extrusionacross the basolateral cell membrane. Sodium enters gall-bladder epithelialcells passively across the luminal membrane down an electrochemicalgradient maintained by its extrusion across the basolateral membrane by asodium pump. Ion replacement studies in rabbit gall bladder have revealedthat active Na+ absorption does not occur when luminal Cl is replaced by avariety of non-transported cations.6 The passive permeability of theluminal cell membrane to Na+ has been found to be too low to account forthe observed transepithelial active sodium flux by diffusional Na+ entry. 14

On the basis of influx studies in rabbit gall bladder'5 non-diffusional Na+entry has been postulated to occur by a one to one electrically neutralcoupled entry mechanism for Na+ and CF. Such a carrier mediated

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mechanism would facilitate charge neutralisation with Cl- entry against anelectrochemical gradient.'6Na+ exit against its electrochemical gradient is facilitated by a Na, K,

ATPase whose activity correlates directly with the rate of fluid transport. 17Its activity, however, is not saturated under in vitro conditions and isdependent on the intracellular Na activity which in turn depends on Na+entry across the luminal membrane, the rate limiting step for trans-epithelial Na+ transport.'4The mechanism of the sodium extrusion at the basolateral membrane is

controversial, both electrogenic (rheogenic)'8 19 and non-electrogenic2"1 21mechanisms have been proposed.

SOLUTE-LINKED WATER ABSORPTIONThe gall-bladder mucosa like numerous other epithelia is able to perform'isotonic' fluid transport - that is, it can transport solute and water betweenequiosmolar bathing media so as to maintain equal tonicities of the bulkmedia.22 Movement of water is believed to be passive and secondary toactive solute movement resulting from osmotic equilibration of transportedsolute within the epithelium. The mechanism and site of the coupling ofsolute and water fluxes by this and other epithelia is unsolved and remainsa central problem of current epithelial research.

In 1967 Diamond and Bossert23 proposed the standing gradient osmoticflow theory to explain the intraepithelial osmotic coupling. According tothis, solute is pumped into the long narrow spaces between adjacentepithelial cells. This creates a hypertonic compartment into which cellularwater is drawn by osmosis resulting in flow towards the serosal end of thelateral intracellular space and a standing osmotic gradient within the spaceunder steady state conditions. Early support for this mechanism was thefinding that the lateral intercellular spaces of rabbit gall bladder (in vitro)were distended during fluid transport and collapsed by procedures whichinhibit transport such as low temperature, ouabain, metabolic inhibitors,and ion replacements.24 Though compatible with the standing gradienttheory changes in cell volume and accummulation in vitro of transportedfluid in the subepithelial space may account for these changes. On the basisof morphological studies in living unfixed frog25 and rabbit26 gall bladder ithas been proposed that widening of the lateral intercellular spaces is afixation artefact and that the paracellular route does not contributesignificantly to isosmotic net fluid absorption.

Hill27 28 has criticised the standing gradient theory on the grounds thatthe epithelial water permeability of membranes adjacent to the lateralintercellular space is insufficient to account for osmotic equilibration acrossthem. In its place he has proposed an electroosmotic theory. As discussedby Diamond29 the above criticism is based on erroneous analysis becauseof inappropriate selection of transport parameters.The rate of NaCI and fluid absorption is enhanced by bicarbonate.3(

Recent studies suggest that HCO3 is required for the maintenance ofintracellular H' which in turn maintains a Na/H exchange. Thismechanism is compatible with the presence of a double ion exchangemediating parallel counter-transport of Na-H and Cl-HCO3 in the apicalmembrane.31 32 The above discussion has considered only the transcellularmovement of ions. In the last decade it has been recognised that ions also

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Gall-bladder water and electrolyte transport and its regulation5

move across epithelia by the paracellular pathway. In 1972 Fromter andDiamond-33 showed by quantitative cable analysis that the transjunctional(paracellular) route in Necturus gall bladder accounted for some 97% ofpassive ion permeation. Their survey of other epithelia showed markeddifferences in junctional tightness on which basis they classified epithelia as'tight' or 'leaky'. The leakiness of gall-bladder tight junctions has also beenshown using electron microscopy. A study in rabbit gall bladder has shownthat lanthanum, used as an electron dense marker, is able to move from thegall-bladder lumen across the tight junction to the lateral intercellularspace without penetrating the epithelial cells.34

FLUID SECRETION BY GALL-BLADDER MUCOSAEarly reports reviewed by Ivy5 documented secretion by gall-bladdermucosa. In particular Burch and Spong35 in 1887 reported observations ongall-bladder secretion in two patients who had undergone chole-cystotomy. The secretion collected was clear to slightly opalescent, almostcolourless, slightly alkaline and contained a high proportion of mucin. Inview of the normal appearance of the gall-bladder wall and the unalteredcomposition of the secretion in one patient over two years these authorsbelieved the secretion to be a normal product of the mucosa acting tolubricate the gall-bladder wall.More than 80 years later Schafer and his colleagues36 reported a similar

secretion in the dog gall bladder after instillation of a crude vibrio choleraeextract. This procedure reversed the direction of transport from a netabsorption of 3-6 ml/h to a net secretion of 05-1 ml/h which continued formore than 24 hours. The secreted fluid was clear, viscid and alkaline beingrich in bicarbonate. Purified cholera toxin has subsequently been reportedto inhibit fluid absorption by isolated guinea pig37 and rabbit38 gallbladders, reversin it to a net secretion only in the former species.Prostaglandins,39 4 prostacyclin,4' and gastrointestinal hormones4244 canalso induce a net fluid secretion by the guinea pig gall bladder in vitro.Secretion has been reported in vivo in the anaesthetised cat afterintravenous infusions of gastrointestinal hormones45 46 and local intra-arterial infusion of prostaglandin E2.47 Gall-bladder secretion after feedinghas been observed in the conscious monkey.'3 The failure of choleratoxin:38 prostaglandins,48 and secretin49 to induce secretion by rabbit gallbladder suggests an absence of a secretory mechanism in this species.The secretion of water and electrolytes by the gall-bladder mucosa is an

active process which can take place against hydrostatic and osmoticgradients5t0 and is inhibited by ouabain. The ionic events occurring duringsecretion have been studied in the guinea pig gall bladder. In this speciesunder non-secretory control conditions bicarbonate is secreted into thegall-bladder lumen in exchange for chloride.30 This transport continuesand is, enhanced during prostaglandin-induced secretion where it isassociated with a considerable reduction in chloride absorption and areversal of sodium and potassium absorption to a net secretion. These ionicchanges are accompanied by an increase in both short circuit current (Isc)and tissue conductance (Gt). Secretion is abolished by omission ofbicarbonate from the bathing solution and is independent of the externalcalcium concentration. These findings suggest that bicarbonate is secretedelectrogenically into the gall-bladder lumen.5'

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Humoral and neural influence on transport

EFFECTS OF BIOLOGICALLY ACTIVE SUBSTANCES ON FLUID TRANSPORTA variety of local mediators have been found to affect the rate of NaCI andwater transport both in vivo and in vitro. Some of these could act toregulate gall-bladder water and electrolyte transfer under physiologicalconditions by modification of NaCl influx, active Na+ extrusion, and/orjunctional permeability. Cyclic AMP has been proposed as a secondmessenger for the effects of several such mediators and has been found inrabbit" and Necturus gall bladder52 to inhibit the NaCl coupled influx, therate limiting step for transepithelial Na+ transport. In addition to effects onluminal membrane function cAMP may also regulate transport byinfluencing tight junction permeability.53

GASTROINTESTINAL PEPTIDESSecretin and extracts of islet cell tumours but not cholecystokinin or gastrinwere reported to inhibit fluid absorption by the isolated rabbit gallbladder. 8 The extent of this inhibitory effect and concentrations of eachsubstance used was unfortunately not documented in this report.Experiments using the isolated guinea pig gall bladder have shown thatnatural porcine secretin, synthetic secretin, PHI (a recently isolatedsecretin-like peptide whose molecuar sequence starts with histidine andends with isoleucine), and natural porcine VIP inhibit fluid absorptionconcentration-dependently with half maximal inhibition values of 1.8, 60,and 8.2 ng/ml for the latter three peptides respectively.42" At the highestconcentrations studied these peptides reversed the direction of transportfrom net absorption to net secretion.

Studies in vivo in the anaesthetised cat have provided similar results.VIP (1 gg/kg/h) infused intravenously inhibited gall-bladder water andelectrolyte transport and reversed its direction to a net secretion, an effectwhich was readily reversible.45 Similar findings were reported with naturalporcine secretin (2 U/kg/h) though the secretory effect was less consistent.Natural porcine cholecystokinin (2 U/kg/h) was without effect ontransport.46A recent study54 has examined the effects of VIP and secretin on cAMP

production by isolated epithelial cells of human and guinea pig gallbladder. VIP was a potent stimulant of cAMP production by humangall-bladder cells with half maximal and tnaximal stimulation at 02 and 10nM respectively. Secretin was also a potent stimulant of cAMP formationby guinea pig but not human gall bladder. The effects of VIP and secretinon fluid transport by human gall bladder have yet to be reported. Theabove findings suggest that VIP-ergic nerves shown by immuno-histochemistry in the gall-bladder wall of several species55 may release VIPto act on receptors on the serosal surface of gall-bladder epithelial cells andthereby modify the direction and rate of transmucosal fluid transport.Glucagon and gastric inhibitory peptide (GIP) which belong to the samehormone family as secretin and VIP have been studied in the cat56 andguinea pig.43 In the latter species glucagon inhibited transport dose-dependently at high concentrations producing half maximal inhibition at4.4 ,ug/ml. The absence of an effect with this peptide in the anaesthetisedcat probably reflects the lower concentration studied. Natural porcine GIP




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Gall-bladder water and electrolyte transport and its regulation

was without effect in both species. A variety of other gastrointestinalpeptides have been studied in the isolated guinea pig gall bladder.Neurotensin, bombesin, motilin, cholecystokinin, caerulein, andsomatostatin were all without effect on absorption. The effects of almostall gastrointestinal peptides on human gall-bladder fluid transport are asyet unreported. Onstad and colleagues58 found an inhibitory effect ofnatural cholecystokinin on transport by gall bladders removed atcholecystectomy. This finding may reflect an increased serosal pressurewithin their everted human gall-bladder preparation rather than a directeffect of cholecystokinin on the epithelium per se.

It is of interest that glucagon has been reported to increase the size of thehuman gall bladder before or after a fatty meal.59 The mechanism of thiseffect is uncertain as in vitro studies on the effect of glucagon on humangall-bladder strips failed to show any effect.60 It is possible that an increasein gall bladder size may result from a secretion into the lumen.The gall-bladder mucosa is subject to a complex series of neural and

endocrine-paracrine regulatory influences during digestion. Of the aboveregulatory peptides whose effects have been studied only VIP and secretinare able to modify gall-bladder fluid transport at concentrations which maybe considered physiological. Peptides without effect on transport in vitrowhen administered alone may, however, act to potentiate or inhibit theeffects of these candidate peptides and other as yet unrecognisedregulatory factors. Thus, for example, though somatostatin had no effecton basal transport it completely reversed the inhibitory effect of VIP andsecretin or absorption.6'

PROSTAGLANDINS AND RELATED SUBSTANCESProstaglandins are synthesised from arachidonic acid released frommembrane phospholipids by the action of phospholipases. Recent researchhas shown that arachidonic acid may be converted via the unstable cyclicendoperoxide intermediates PGG2 and PGH2 not only to prostaglandinsbut to other potent biologically active prostanoids the thromboxanes andprostacyclin. 2

The effects of prostaglandins of the E and F series have been studied invitro using rabbit and guinea pig gall bladder preparations. In rabbit gallbladder48 serosal application of prostaglandins E,, E2, or F2,X inhibitedfluid absorption dose-dependently. The response to prostaglandin E was 10times more potent in the presence of indomethacin, an inhibitor ofendogenous prostaglandin formation. Prostaglandin E, and prostaglandinE2 were equipotent, 100 fold more effective than prostaglandin F21, andinhibited fluid absorption at a maximum by 50%. On luminal applicationthe two E prostaglandins had only weak inhibitory effect. A similar rankpotency and lower efficacy of the above prostaglandins on mucosal ascompared with serosal application has been reported for guinea pig. Theinhibitory potency of prostaglandins on fluid absorption was found to varyinversely with animal body weight by one to two orders of magnitudebetween younger lighter animals and older heavier animals.4" In contrastwith the findings with rabbit gall bladder prostaglandins E1, E2, and F21,were able to totally inhibit fluid absorption, reversing it to a netsecretion.39 40 These prostaglandins and prostaglandin A, were lesseffective on luminal than on serosal application.

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Prostaglandin E2 (5 gg/kg/min) infused intraarterially into theanaesthetised cat reversibly inhibited net gall-bladder absorption and inhalf the animals tested reversed the direction of transport to a netsecretion.47The above studies show that prostaglandins have potent effects on

gall-bladder transport. Prostaglandin E and prostaglandin F-likesubstances have been isolated from the mucosa and muscle of pathologicalhuman gall bladders63 and from homogenates of guinea pig gall bladder(J R Wood and I F Stamford, unpublished). The ability of indomethacin, aprostaglandin synthesis inhibitor, to antagonise inhibition of gall-bladderfluid absorption by aracidonic acid64 provides further evidence forendogenous synthesis of prostanoids by gall bladder. Whether or notprostanoid formation acts to modify transport under physiologicalconditions is unknown. There is, however, good evidence to support a rolefor prostaglandins and other prostanoids in the pathological changes ingall-bladder transport observed in cholecystitis. This will be considered in alater section.

BILE ACIDSBile acids are present in the gall-bladder lumen in high concentration.Three studies have examined their effects on gall-bladder fluid absorption.In dog gall bladder65 in vivo 16-7 mM taurodeoxycholate or taurocheno-deoxycholate applied intraluminally completely abolished net waterabsorption. Taurocholate was ineffective at this concentration but had asmall inhibitory effect at 40 mM. In contrast with findings in the intestinethese substances did not induce a net fluid secretion. The lack of effect oftaurodeoxycholate on rabbit gall-bladder66 transport may reflect therelatively low concentration studied. In the guinea pig gall bladder in vitrochenodeoxycholate (0.3-2.5 mM) and its glycine conjugate (0.6-S5 mM)inhibited fluid absorption concentration-dependently to a maximum of80%. Chenodeoxycholate also inhibited fluid absorption when appliedserosally but was less potent than on mucosal application. Glycocholatewas without effect and the inhibitory effect of cholate at high concen-trations may result from its contamination by deoxycholate.67 The effectsof bile acids on water and electrolyte transport under physiologicalconditions will be modified by other constituents of bile. In particularlecithin has been shown to block the inhibitory effect of taurodeoxycholateon water absorption by dog gall bladder. Effects of bile acids ongall-bladder concentrating function are therefore more likely to haverelevance to pathological conditions resulting in their deconjugation withinthe gall-bladder lumen than to physiological events.

HORMONES AND OTHER AGENTSFemale sex hormones have been reported to inhibit gall-bladder fluidabsorption in vitro.68 69 The concentrations of 171 oestradiol andprogesterone used in these experiments are unfortunately pharmacologicaland provide no information concerning any possible physiological effects.It is not known whether gall-bladder absorptive function is influenced bydifferent phases of the ovulatory cycle. Early studies, however, suggestthat gall-bladder concentrating function may be impaired during pregnancyand parturition.




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Gall-bladder wvater antd electrolyte tranlsport and its reguilation

Riegel and her colleagues71" studied the composition of gall-bladder bilein women at term and found changes consistent with impaired gall-bladderconcentrating function. Potter7' in 1936 observed that the gall bladder inpregnant women undergoing caesarian section was distended, containingbile of similar composition to hepatic bile.A miscellany of other hormones and biologically active substances

including prolactin.72 oxytocin and ADH,6 angiotensin II,7" andserotonin77 inhibit absorption or are without effect. There is no evidence atpresent to support a role for any of these substances in the physiologicalregulation of gall-bladder water and electrolyte transport.

INFLUENCE OF THE AUTONOMIC NERVOUS SYSTEMAdrenergic cholinergic and peptidergic nerve fibres have been shown ingall bladder. Nerve fibres with noradrenergic immunofluorescence havebeen visualised in the gall-bladder wall using histological techniques.78 Thetissue concentrations of noradrenaline in the extrahepatic biliary tract havebeen reported to exceed those in the small intestine.75 Studies of thedistribution of adrenergic fibres in the gall-bladder wall have shown adirect and an indirect system.79 The nerves in the direct system terminatemainly on blood vessels and smooth muscle cells and the fibres in theindirect system are believed to act on intrinsic excitatory neurones.Kyosola and Penttila78 in the human gall bladder found a sparsenoradrenergic innervation of the mucosa and a dense innervation of themuscle layer. Cholinergic nerve fibres have also been shown in thegall-bladder wall by histological methods.8" The possible role of nervefibres immunoreactive to VIP has already been considered.The adrenergic nerve supply to the gall bladder travels in the splanchnic

nerves but as adrenergic fibres have also been visualised in the vagusnerveX a part of the adrenergic nerve supply ma,y take this route.Cholinergic fibres are received from the vagus nerves. " Peptidergic fibreshave been found in the vagus nerves82 and electrical stimulation of thesenerves is known to release VIP and gastrin into the portal blood.8>85Peptidergic fibres are also found in the splanchnic nerves,86 electricalstimulation of which has been found to reduce the VIP concentration in theportal blood.Noradrenaline increased net water absorption by the everted human gall

bladder,8 the gall bladder of the anaesthetised cat,87 but not by theisolated guinea pig gall bladder.88 Acetylcholine had no effect on watertransport by the guinea pig gall bladder88 in vitro or the cat gall bladder89 in1'ivo in doses causing gall-bladder contraction. Of other possible neuro-transmitters gastrin has been reported to reduce net water absorption bythe dog gall bladder in vitro9" and VIP has potent effects considered above.

It has been recently found that electrical stimulation of the splanchnicnerves stimulates the rate of water absorption by the gall bladder of theanaesthetised cat, an effect which can be abolished by alpha-adrenergicreceptor blockade. The precise site of action of the sympathetic nerves onnet water transport by the gall bladder is unknown. Apart from a possibledirect effect on mucosal cells, sympathetic nerves may act on local gangliato inhibit release of a neurotransmitter which inhibits water absorption. Apossible transmitter set free by local reflexes is VIP.

Westphal and coworkers9' in 1931 reported that electrical stimulation of

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the vagus could increase water absorption by the dog gall bladder. Theirresults were not consistent, however, and in a few experiments a reducedwater transport was noted. In a recent study89 92 electrical stimulation ofthe cervical vagus nerves in the cat failed to influence the rate of fluidtransport in the gall bladder measured by a perfusion technique. Using thesame technique vagal stimulation significantly reduced the net waterabsorption in atropinised animals. Electrical stimulation of the vagusnerves at the level of the neck will influence the gall bladder directly. Acomplex of the direct effects of the nerve fibres might, however, be maskedby secondary effects because of released gastrointestinal peptides andother blood borne factors. Evidently there seems to be a non-cholinergicmechanism capable of reducing net water absorption by the gall bladder.

Histological study of the gall-bladder mucus secretion93 has shown anincreased discharge of glycogen granules in response to cholinergic drugswhile adrenergic or alpha-adrenergic blocking drugs had no effect.

Physiological changes in transport

Classical physiology views the gall-bladder mucosa as continuouslyabsorbing water. Several studies, however, suggest that gall-bladdertransport is subject to physiological regulation. Johnston and coworkers94in 1932 found that the hourly absorption of water by dog gall bladder wasthree times greater during the day than at night during sleep. Morerecently Lindemann and Rund95 attempted to study the absorption ofsodium chloride from the gall bladder of the dog after feeding but wereunable to detect any variation in the transport rate. They studied only fourdogs, however, and the report is most inconclusive. In a recent study'3 theinfluence of fasting and feeding on the concentrating function of the gallbladder was studied in conscious monkeys. During the day fasting animalshad a net hourly absorption rate corresponding to one third of thefasting gall-bladder volume. Feeding resulted in a reversal of the directionof gall-bladder transport from a net absorption to a net secretion into thegall-bladder lumen. This study also confirmed the findings of Johnston andcoworkers that compared with the awake fasting state net water absorptionfrom the gall bladder was reduced at night during sleep.The net water transport across the gall-bladder wall may be influenced

by both humoral factors and autonomic nerves as seen above. Thegall-bladder secretory response to feeding may result from an increasedrelease of VIP from intramural nerves. Exogenous VIP as discussed abovecan induce a net fluid secretion into the gall bladder. VIP receptors havebeen shown on the epithelial cells and histochemical studies have visualisedVIP-containing nerve fibres in close proximity to the gall-bladderepithelium. The greater net water absorption during daytime comparedwith sleeping may be explained by a general increase in the activity of thesympathetic nervous system as alpha-adrenergic stimulation has beenshown to increase net water absorption in the cat gall bladder.96

Variations in the concentrating function of the gall bladder may affectthe enterohepatic circulation of substances such as bile salts. In addition tothe frequency of gall-bladder contraction a net secretion by the gall bladdermay influence the rate of bile acid entry into the gut. An increased net fluidabsorption under conditions of increased adrenergic activity would have




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Gall-bladder water and electrolyte transport and its regulation

the opposite effect. Fluid secretion into the gall bladder resulting indilution of the organic constituents of bile might be of importance forefficient evacuation of the gall bladder after a meal, and may also helpeliminate precipitation nuclei that form in the gall-bladder lumen.

Pathological changes in transport

CONGENITAL TRANSPORT DEFECTA recent study97 has attempted to examine the concentrating ability of thegall bladder of a child with congenital chloridorrhoea, a rare autosomalrecessive disturbance of intestinal chloride transport. Gall-bladdertransport was assessed indirectly by measurement of duodenal bile acidconcentrations before and after presumed gall-bladder contractionstimulated by exogenous cholecystokinin. The absence of a change induodenal bile acid concentration in this child, in marked contrast with theincrease in three control children was taken as evidence for a defect ingall-bladder electrolyte transport. This conclusion must, however, remainin doubt in view of the absence of evidence to substantiate gall bladderevacuation in the affected child.

NEUROENDOCRINE TUMOUR SYNDROMESAbnormalities of gall-bladder function have been reported in the VernerMorrison syndrome (pancreatic cholera or WDHA syndrome). Patientswith this syndrome have raised circulating VIP concentrations and largeatonic gall bladders98 99 containing a dilute bile rich in bicarbonate.°These changes may be accounted for by a relaxant effect of VIP ongall-bladder muscle, by its ability to antagonise the contractile effects ofcholecystokinin,'10-1'05 by its effects on gall-bladder fluid transport similarto those described above for 1uinea pig and cat, and by changes in thecomposition of hepatic bile. 16 Though changes in bile compositionhave not yet been reported in association with hypersecretion of othergastrointestinal hormones it is of interest that cholelithiasis is a feature ofthe somatostatinoma syndrome.108 Somatostatin has been reported toreverse cholecystokinin induced gall-bladder contraction in the dog invivo109 but not in vitro. 105 It is also able to reverse the inhibitory effect ofVIP and secretin on gall-bladder fluid transport.61 Whether or not thesusceptibility to cholelithiasis results from reduced postprandial gallbladder evacuation or from impaired regulation of gall-bladder fluidtransport remains to be determined.

GALL-BLADDER FLUID TRANSPORT IN CHOLECYSTITISThe absorptive function of the gall bladder in gall-stone disease in man isknown only from visualisation at cholecystography or from studies in vitro.The general consensus from radiological studies is that the gall bladder canbe visualised in chronic but not acute cholecystitis. In a study of transportby human gall bladders excised at cholecystectomy absorptive functioncorrelated with histological and clinical findings."1' Patients with moremarked clinical findings were found to have more extensive histologicalchanges and poor absorptive function in the gall bladder. In experimentalcholelithiasis in the rabbit Kyd and Bouchier,112 however, found nodifference in the rate of water absorption between stone forming and

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control gall bladders. Lee in a subsequent study in isolated guinea pig andrabbit gall bladder has reported an enhanced water absorption per unitgall-bladder weight during lithogenesis."13 This in vitro function may not becomparable with the ability of the gall bladder to absorb water andelectrolytes in vivo where blood supply, lymphatic drainage and nervousand humoral factors influence its function.

In a recent study"4 fluid transport by the gall bladder was studied inexperimental cholecystitis in the cat. Cholecystitis was induced byimplanting human gall stones into the cat gall bladders. Three months laterthe concentrating function of the gall bladder was studied in vivo in theanaesthetised animal. It was found that in animals with a patent cystic ductthe concentrating function of the gall bladder was intact despite a slight ormoderate inflammation of the mucosa. In contrast, animals with gall-stoneinduced cystic duct obstruction whose gall-bladder mucosa was markedlyinflamed continuously secreted fluid into the gall-bladder lumen, forming ahydrops. Indomethacin, a prostaglandin synthetase inhibitor, promptlyreversed this fluid secretion to an absorption suggesting that endogenousprostaglandin formation may be responsible for the observed fluidtransport change. In a recent study in dogs115 it was found that obstructionof the gall bladder in combination with infection of its contents induced acontinuous fluid secretion into its lumen that was sustained for severaldays. This secretion was markedly reduced by indomethacin furthersupporting the role of prostaglandins in secretion by the inflamed gallbladder.A factor considered important in the pathophysiology of cholecystitis is

formation of lysolecithin by hydrolysis of phospholipids in the gallbladder."16 It has recently been reported' "9 that addition of lysolethicin toan electrolyte solution in the gall-bladder lumen at a concentrationcomparable with that found in the bile of patients with acutecholecystitis"8S reversed the direction of transport to a net secretion. Thisfluid secretion was abolished by indomethacin suggesting that at least partof the change in fluid transport may result from endogenous prostaglandinformation.

In acute cholecystitis the gall-bladder neck is often obstructed by a gallstone. A reversal of the direction of fluid transport across the gall-bladdermucosa to a net secretion into the lumen will cause distension of theobstructed gall bladder. Distension has recently been reported to stimulateprostaglandins synthesis by the gall-bladder wall.'19 The clinical course ofacute cholecystitis with necrosis and gall-bladder perforation can beexplained by these changes. 120 This hypothesis is further supported by thefinding that the intraluminal pressure in the gall bladder in acutecholecystitis is markedly raised, sometimes to values exceeding 90 mmHg. 121 122

J R WOOD AND J SVANVIKDepartment of SurgeryKings College Hospital Medical SchoolUniversity of London, LondonandDepartment of Surgery IUniversity of GoteborgGoteborg, Sweden Received for publication 2 September 1982

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Progress report - Gut · Gut, 1983, 24, 579-593 Progress report Gall-bladderwaterandelectrolyte transportandits regulation Diemerbroek' in 1672 appreciated that bile entered the gall