Gall-bladder water and electrolyte transport and its regulation

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Gut, 1983, 24, 579-593
Progress report
Gall-bladder water and electrolyte
transport and its regulation
Diemerbroek' in 1672 appreciated that bile entered the gall bladder to
'acquire greater strength and digestive power'. A study by Rous and
McMaster2 in 1921 and later work by Ravdin and his coworkers3 4
provided direct experimental support for the notion that the gall bladder
concentrates hepatic bile by selective reabsorption of bile constituents.
These early studies have been reviewed in detail by Ivy.5 The nature of
water and electrolyte absorption by gall-bladder mucosa has been
extensively studied by Diamond and his colleagues whose work has
provided an important basis for understanding of transport by this and
other more complex epithelia.68 Subsequent studies using isotope and
electrophysiological techniques which have sought to define the ionic basis
for salt and water transport by gall bladder are the subject of several
reviews.9-11 Recent experiments on the effects of gastrointestinal
hormones and other secretagogues on gall-bladder transport have
established that the gall bladder, like the intestine, is able to reverse the
direction of its transport from a net absorption to a net secretion.'2 The
finding that feeding in the conscious monkey can abolish gall-bladder fluid
absorption and reverse it to a net secretion provides for the first time direct
evidence that the rate and direction of fluid absorption by the gall-bladder
mucosa are subject to physiological regulation during digestion. 13
In this report we review recent studies contributing to the understanding
of fluid and electrolyte transport by the gall bladder with particular
reference to physiological control mechanisms and pathological changes
which modify it.
Transport mechanisms
SODIUM AND CHLORIDE TRANSPORT
The rate of transcellular sodium transport depends on the rate of sodium
entry across the luminal cell membrane and the active sodium extrusion
across the basolateral cell membrane. Sodium enters gall-bladder epithelial
cells passively across the luminal membrane down an electrochemical
gradient maintained by its extrusion across the basolateral membrane by a
sodium pump. Ion replacement studies in rabbit gall bladder have revealed
that active Na+ absorption does not occur when luminal Cl is replaced by a
variety of non-transported cations.6 The passive permeability of the
luminal cell membrane to Na+ has been found to be too low to account for
the 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 neutral
coupled entry mechanism for Na+ and CF. Such a carrier mediated
579
580
Wood and Svanvik
mechanism would facilitate charge neutralisation with Cl- entry against an
electrochemical gradient.'6
Na+ exit against its electrochemical gradient is facilitated by a Na, K,
ATPase whose activity correlates directly with the rate of fluid transport. 17
Its activity, however, is not saturated under in vitro conditions and is
dependent on the intracellular Na activity which in turn depends on Na+
entry across the luminal membrane, the rate limiting step for transepithelial Na+ transport.'4
The mechanism of the sodium extrusion at the basolateral membrane is
controversial, both electrogenic (rheogenic)'8 19 and non-electrogenic2"1 21
mechanisms have been proposed.
SOLUTE-LINKED WATER ABSORPTION
The gall-bladder mucosa like numerous other epithelia is able to perform
'isotonic' fluid transport - that is, it can transport solute and water between
equiosmolar bathing media so as to maintain equal tonicities of the bulk
media.22 Movement of water is believed to be passive and secondary to
active solute movement resulting from osmotic equilibration of transported
solute within the epithelium. The mechanism and site of the coupling of
solute and water fluxes by this and other epithelia is unsolved and remains
a central problem of current epithelial research.
In 1967 Diamond and Bossert23 proposed the standing gradient osmotic
flow theory to explain the intraepithelial osmotic coupling. According to
this, solute is pumped into the long narrow spaces between adjacent
epithelial cells. This creates a hypertonic compartment into which cellular
water is drawn by osmosis resulting in flow towards the serosal end of the
lateral intracellular space and a standing osmotic gradient within the space
under steady state conditions. Early support for this mechanism was the
finding that the lateral intercellular spaces of rabbit gall bladder (in vitro)
were distended during fluid transport and collapsed by procedures which
inhibit transport such as low temperature, ouabain, metabolic inhibitors,
and ion replacements.24 Though compatible with the standing gradient
theory changes in cell volume and accummulation in vitro of transported
fluid in the subepithelial space may account for these changes. On the basis
of morphological studies in living unfixed frog25 and rabbit26 gall bladder it
has been proposed that widening of the lateral intercellular spaces is a
fixation artefact and that the paracellular route does not contribute
significantly to isosmotic net fluid absorption.
Hill27 28 has criticised the standing gradient theory on the grounds that
the epithelial water permeability of membranes adjacent to the lateral
intercellular space is insufficient to account for osmotic equilibration across
them. In its place he has proposed an electroosmotic theory. As discussed
by Diamond29 the above criticism is based on erroneous analysis because
of 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 of
intracellular H' which in turn maintains a Na/H exchange. This
mechanism is compatible with the presence of a double ion exchange
mediating parallel counter-transport of Na-H and Cl-HCO3 in the apical
membrane.31 32 The above discussion has considered only the transcellular
movement of ions. In the last decade it has been recognised that ions also
Gall-bladder water and electrolyte transport and its regulation5
581
move across epithelia by the paracellular pathway. In 1972 Fromter and
Diamond-33 showed by quantitative cable analysis that the transjunctional
(paracellular) route in Necturus gall bladder accounted for some 97% of
passive ion permeation. Their survey of other epithelia showed marked
differences in junctional tightness on which basis they classified epithelia as
'tight' or 'leaky'. The leakiness of gall-bladder tight junctions has also been
shown using electron microscopy. A study in rabbit gall bladder has shown
that lanthanum, used as an electron dense marker, is able to move from the
gall-bladder lumen across the tight junction to the lateral intercellular
space without penetrating the epithelial cells.34
FLUID SECRETION BY GALL-BLADDER MUCOSA
Early reports reviewed by Ivy5 documented secretion by gall-bladder
mucosa. In particular Burch and Spong35 in 1887 reported observations on
gall-bladder secretion in two patients who had undergone cholecystotomy. The secretion collected was clear to slightly opalescent, almost
colourless, slightly alkaline and contained a high proportion of mucin. In
view of the normal appearance of the gall-bladder wall and the unaltered
composition of the secretion in one patient over two years these authors
believed the secretion to be a normal product of the mucosa acting to
lubricate 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 cholerae
extract. This procedure reversed the direction of transport from a net
absorption of 3-6 ml/h to a net secretion of 05-1 ml/h which continued for
more than 24 hours. The secreted fluid was clear, viscid and alkaline being
rich in bicarbonate. Purified cholera toxin has subsequently been reported
to inhibit fluid absorption by isolated guinea pig37 and rabbit38 gall
bladders, reversin4 it to a net secretion only in the former species.
Prostaglandins,39 prostacyclin,4' and gastrointestinal hormones4244 can
also induce a net fluid secretion by the guinea pig gall bladder in vitro.
Secretion has been reported in vivo in the anaesthetised cat after
intravenous infusions of gastrointestinal hormones45 46 and local intraarterial infusion of prostaglandin E2.47 Gall-bladder secretion after feeding
has been observed in the conscious monkey.'3 The failure of cholera
toxin:38 prostaglandins,48 and secretin49 to induce secretion by rabbit gall
bladder 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 osmotic
gradients5t0 and is inhibited by ouabain. The ionic events occurring during
secretion have been studied in the guinea pig gall bladder. In this species
under non-secretory control conditions bicarbonate is secreted into the
gall-bladder lumen in exchange for chloride.30 This transport continues
and is, enhanced during prostaglandin-induced secretion where it is
associated with a considerable reduction in chloride absorption and a
reversal of sodium and potassium absorption to a net secretion. These ionic
changes are accompanied by an increase in both short circuit current (Isc)
and tissue conductance (Gt). Secretion is abolished by omission of
bicarbonate from the bathing solution and is independent of the external
calcium concentration. These findings suggest that bicarbonate is secreted
electrogenically into the gall-bladder lumen.5'
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Wood and Svanvik
Humoral and neural influence on transport
EFFECTS OF BIOLOGICALLY ACTIVE SUBSTANCES ON FLUID TRANSPORT
A variety of local mediators have been found to affect the rate of NaCI and
water transport both in vivo and in vitro. Some of these could act to
regulate gall-bladder water and electrolyte transfer under physiological
conditions by modification of NaCl influx, active Na+ extrusion, and/or
junctional permeability. Cyclic AMP has been proposed as a second
messenger for the effects of several such mediators and has been found in
rabbit" and Necturus gall bladder52 to inhibit the NaCl coupled influx, the
rate limiting step for transepithelial Na+ transport. In addition to effects on
luminal membrane function cAMP may also regulate transport by
influencing tight junction permeability.53
GASTROINTESTINAL PEPTIDES
Secretin and extracts of islet cell tumours but not cholecystokinin or gastrin
were reported to inhibit fluid absorption by the isolated rabbit gall
bladder. 8 The extent of this inhibitory effect and concentrations of each
substance used was unfortunately not documented in this report.
Experiments using the isolated guinea pig gall bladder have shown that
natural porcine secretin, synthetic secretin, PHI (a recently isolated
secretin-like peptide whose molecuar sequence starts with histidine and
ends with isoleucine), and natural porcine VIP inhibit fluid absorption
concentration-dependently with half maximal inhibition values of 1.8, 60,
and 8.2 ng/ml for the latter three peptides respectively.42" At the highest
concentrations studied these peptides reversed the direction of transport
from 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 and
electrolyte transport and reversed its direction to a net secretion, an effect
which was readily reversible.45 Similar findings were reported with natural
porcine secretin (2 U/kg/h) though the secretory effect was less consistent.
Natural porcine cholecystokinin (2 U/kg/h) was without effect on
transport.46
A recent study54 has examined the effects of VIP and secretin on cAMP
production by isolated epithelial cells of human and guinea pig gall
bladder. VIP was a potent stimulant of cAMP production by human
gall-bladder cells with half maximal and tnaximal stimulation at 02 and 10
nM respectively. Secretin was also a potent stimulant of cAMP formation
by guinea pig but not human gall bladder. The effects of VIP and secretin
on fluid transport by human gall bladder have yet to be reported. The
above findings suggest that VIP-ergic nerves shown by immunohistochemistry in the gall-bladder wall of several species55 may release VIP
to act on receptors on the serosal surface of gall-bladder epithelial cells and
thereby modify the direction and rate of transmucosal fluid transport.
Glucagon and gastric inhibitory peptide (GIP) which belong to the same
hormone family as secretin and VIP have been studied in the cat56 and
guinea pig.43 In the latter species glucagon inhibited transport dosedependently at high concentrations producing half maximal inhibition at
4.4 ,ug/ml. The absence of an effect with this peptide in the anaesthetised
cat probably reflects the lower concentration studied. Natural porcine GIP
583
was without effect in both species. A variety of other gastrointestinal
peptides have been studied in the isolated guinea pig gall bladder.
Neurotensin, bombesin, motilin, cholecystokinin, caerulein, and
somatostatin were all without effect on absorption. The effects of almost
all gastrointestinal peptides on human gall-bladder fluid transport are as
yet unreported. Onstad and colleagues58 found an inhibitory effect of
natural cholecystokinin on transport by gall bladders removed at
cholecystectomy. This finding may reflect an increased serosal pressure
within their everted human gall-bladder preparation rather than a direct
effect of cholecystokinin on the epithelium per se.
It is of interest that glucagon has been reported to increase the size of the
human gall bladder before or after a fatty meal.59 The mechanism of this
effect is uncertain as in vitro studies on the effect of glucagon on human
gall-bladder strips failed to show any effect.60 It is possible that an increase
in 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 above
regulatory peptides whose effects have been studied only VIP and secretin
are able to modify gall-bladder fluid transport at concentrations which may
be considered physiological. Peptides without effect on transport in vitro
when administered alone may, however, act to potentiate or inhibit the
effects of these candidate peptides and other as yet unrecognised
regulatory factors. Thus, for example, though somatostatin had no effect
on basal transport it completely reversed the inhibitory effect of VIP and
secretin or absorption.6'
PROSTAGLANDINS AND RELATED SUBSTANCES
Prostaglandins are synthesised from arachidonic acid released from
membrane phospholipids by the action of phospholipases. Recent research
has shown that arachidonic acid may be converted via the unstable cyclic
endoperoxide intermediates PGG2 and PGH2 not only to prostaglandins
but to other potent biologically active prostanoids the thromboxanes and
prostacyclin. 2
The effects of prostaglandins of the E and F series have been studied in
vitro using rabbit and guinea pig gall bladder preparations. In rabbit gall
bladder48 serosal application of prostaglandins E,, E2, or F2,X inhibited
fluid absorption dose-dependently. The response to prostaglandin E was 10
times more potent in the presence of indomethacin, an inhibitor of
endogenous prostaglandin formation. Prostaglandin E, and prostaglandin
E2 were equipotent, 100 fold more effective than prostaglandin F21, and
inhibited fluid absorption at a maximum by 50%. On luminal application
the two E prostaglandins had only weak inhibitory effect. A similar rank
potency and lower efficacy of the above prostaglandins on mucosal as
compared with serosal application has been reported for guinea pig. The
inhibitory potency of prostaglandins on fluid absorption was found to vary
inversely with animal body weight by one to two orders of magnitude
between younger lighter animals and older heavier animals.4" In contrast
with the findings with rabbit gall bladder prostaglandins E1, E2, and F21,
were able to totally inhibit fluid absorption, reversing it to a net
secretion.39 40 These prostaglandins and prostaglandin A, were less
effective on luminal than on serosal application.
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Wood and Svanvik
Prostaglandin E2 (5 gg/kg/min) infused intraarterially into the
anaesthetised cat reversibly inhibited net gall-bladder absorption and in
half the animals tested reversed the direction of transport to a net
secretion.47
The above studies show that prostaglandins have potent effects on
gall-bladder transport. Prostaglandin E and prostaglandin F-like
substances have been isolated from the mucosa and muscle of pathological
human gall bladders63 and from homogenates of guinea pig gall bladder
(J R Wood and I F Stamford, unpublished). The ability of indomethacin, a
prostaglandin synthesis inhibitor, to antagonise inhibition of gall-bladder
fluid absorption by aracidonic acid64 provides further evidence for
endogenous synthesis of prostanoids by gall bladder. Whether or not
prostanoid formation acts to modify transport under physiological
conditions is unknown. There is, however, good evidence to support a role
for prostaglandins and other prostanoids in the pathological changes in
gall-bladder transport observed in cholecystitis. This will be considered in a
later section.
BILE ACIDS
Bile 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 taurochenodeoxycholate applied intraluminally completely abolished net water
absorption. Taurocholate was ineffective at this concentration but had a
small inhibitory effect at 40 mM. In contrast with findings in the intestine
these substances did not induce a net fluid secretion. The lack of effect of
taurodeoxycholate on rabbit gall-bladder66 transport may reflect the
relatively low concentration studied. In the guinea pig gall bladder in vitro
chenodeoxycholate (0.3-2.5 mM) and its glycine conjugate (0.6-S5 mM)
inhibited fluid absorption concentration-dependently to a maximum of
80%. Chenodeoxycholate also inhibited fluid absorption when applied
serosally but was less potent than on mucosal application. Glycocholate
was without effect and the inhibitory effect of cholate at high concentrations may result from its contamination by deoxycholate.67 The effects
of bile acids on water and electrolyte transport under physiological
conditions will be modified by other constituents of bile. In particular
lecithin has been shown to block the inhibitory effect of taurodeoxycholate
on water absorption by dog gall bladder. Effects of bile acids on
gall-bladder concentrating function are therefore more likely to have
relevance to pathological conditions resulting in their deconjugation within
the gall-bladder lumen than to physiological events.
HORMONES AND OTHER AGENTS
Female sex hormones have been reported to inhibit gall-bladder fluid
absorption in vitro.68 69 The concentrations of 171 oestradiol and
progesterone used in these experiments are unfortunately pharmacological
and provide no information concerning any possible physiological effects.
It is not known whether gall-bladder absorptive function is influenced by
different phases of the ovulatory cycle. Early studies, however, suggest
that gall-bladder concentrating function may be impaired during pregnancy
and parturition.
Gall-bladder wvater antd electrolyte tranlsport and its reguilation
585
Riegel and her colleagues71" studied the composition of gall-bladder bile
in women at term and found changes consistent with impaired gall-bladder
concentrating function. Potter7' in 1936 observed that the gall bladder in
pregnant women undergoing caesarian section was distended, containing
bile of similar composition to hepatic bile.
A miscellany of other hormones and biologically active substances
angiotensin II,7" and
including prolactin.72 oxytocin and ADH,6
serotonin77 inhibit absorption or are without effect. There is no evidence at
present to support a role for any of these substances in the physiological
regulation of gall-bladder water and electrolyte transport.
INFLUENCE OF THE AUTONOMIC NERVOUS SYSTEM
Adrenergic cholinergic and peptidergic nerve fibres have been shown in
gall bladder. Nerve fibres with noradrenergic immunofluorescence have
been visualised in the gall-bladder wall using histological techniques.78 The
tissue concentrations of noradrenaline in the extrahepatic biliary tract have
been reported to exceed those in the small intestine.75 Studies of the
distribution of adrenergic fibres in the gall-bladder wall have shown a
direct and an indirect system.79 The nerves in the direct system terminate
mainly on blood vessels and smooth muscle cells and the fibres in the
indirect system are believed to act on intrinsic excitatory neurones.
Kyosola and Penttila78 in the human gall bladder found a sparse
noradrenergic innervation of the mucosa and a dense innervation of the
muscle layer. Cholinergic nerve fibres have also been shown in the
gall-bladder wall by histological methods.8" The possible role of nerve
fibres 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 vagus
nerveX
a
part of the adrenergic
nerve
supply ma,y
take this route.
Cholinergic fibres are received from the vagus nerves. " Peptidergic fibres
have been found in the vagus nerves82 and electrical stimulation of these
nerves is known to release VIP and gastrin into the portal blood.8>85
Peptidergic fibres are also found in the splanchnic nerves,86 electrical
stimulation of which has been found to reduce the VIP concentration in the
portal blood.
Noradrenaline increased net water absorption by the everted human gall
bladder,8 the gall bladder of the anaesthetised cat,87 but not by the
isolated guinea pig gall bladder.88 Acetylcholine had no effect on water
transport by the guinea pig gall bladder88 in vitro or the cat gall bladder89 in
1'ivo in doses causing gall-bladder contraction. Of other possible neurotransmitters gastrin has been reported to reduce net water absorption by
the dog gall bladder in vitro9" and VIP has potent effects considered above.
It has been recently found that electrical stimulation of the splanchnic
nerves stimulates the rate of water absorption by the gall bladder of the
anaesthetised cat, an effect which can be abolished by alpha-adrenergic
receptor blockade. The precise site of action of the sympathetic nerves on
net water transport by the gall bladder is unknown. Apart from a possible
direct effect on mucosal cells, sympathetic nerves may act on local ganglia
to inhibit release of a neurotransmitter which inhibits water absorption. A
possible transmitter set free by local reflexes is VIP.
Westphal and coworkers9' in 1931 reported that electrical stimulation of
586
Wood and Svanvik
the vagus could increase water absorption by the dog gall bladder. Their
results were not consistent, however, and in a few experiments a reduced
water transport was noted. In a recent study89 92 electrical stimulation of
the cervical vagus nerves in the cat failed to influence the rate of fluid
transport in the gall bladder measured by a perfusion technique. Using the
same technique vagal stimulation significantly reduced the net water
absorption in atropinised animals. Electrical stimulation of the vagus
nerves at the level of the neck will influence the gall bladder directly. A
complex of the direct effects of the nerve fibres might, however, be masked
by secondary effects because of released gastrointestinal peptides and
other blood borne factors. Evidently there seems to be a non-cholinergic
mechanism capable of reducing net water absorption by the gall bladder.
Histological study of the gall-bladder mucus secretion93 has shown an
increased discharge of glycogen granules in response to cholinergic drugs
while adrenergic or alpha-adrenergic blocking drugs had no effect.
Physiological changes in transport
Classical physiology views the gall-bladder mucosa as continuously
absorbing water. Several studies, however, suggest that gall-bladder
transport is subject to physiological regulation. Johnston and coworkers94
in 1932 found that the hourly absorption of water by dog gall bladder was
three times greater during the day than at night during sleep. More
recently Lindemann and Rund95 attempted to study the absorption of
sodium chloride from the gall bladder of the dog after feeding but were
unable to detect any variation in the transport rate. They studied only four
dogs, however, and the report is most inconclusive. In a recent study'3 the
influence of fasting and feeding on the concentrating function of the gall
bladder was studied in conscious monkeys. During the day fasting animals
had a net hourly absorption rate corresponding to one third of the
fasting gall-bladder volume. Feeding resulted in a reversal of the direction
of gall-bladder transport from a net absorption to a net secretion into the
gall-bladder lumen. This study also confirmed the findings of Johnston and
coworkers that compared with the awake fasting state net water absorption
from 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. The
gall-bladder secretory response to feeding may result from an increased
release of VIP from intramural nerves. Exogenous VIP as discussed above
can induce a net fluid secretion into the gall bladder. VIP receptors have
been shown on the epithelial cells and histochemical studies have visualised
VIP-containing nerve fibres in close proximity to the gall-bladder
epithelium. The greater net water absorption during daytime compared
with sleeping may be explained by a general increase in the activity of the
sympathetic nervous system as alpha-adrenergic stimulation has been
shown to increase net water absorption in the cat gall bladder.96
Variations in the concentrating function of the gall bladder may affect
the enterohepatic circulation of substances such as bile salts. In addition to
the frequency of gall-bladder contraction a net secretion by the gall bladder
may influence the rate of bile acid entry into the gut. An increased net fluid
absorption under conditions of increased adrenergic activity would have
587
the opposite effect. Fluid secretion into the gall bladder resulting in
dilution of the organic constituents of bile might be of importance for
efficient evacuation of the gall bladder after a meal, and may also help
eliminate precipitation nuclei that form in the gall-bladder lumen.
Pathological changes in transport
CONGENITAL TRANSPORT DEFECT
A recent study97 has attempted to examine the concentrating ability of the
gall bladder of a child with congenital chloridorrhoea, a rare autosomal
recessive disturbance of intestinal chloride transport. Gall-bladder
transport was assessed indirectly by measurement of duodenal bile acid
concentrations before and after presumed gall-bladder contraction
stimulated by exogenous cholecystokinin. The absence of a change in
duodenal bile acid concentration in this child, in marked contrast with the
increase in three control children was taken as evidence for a defect in
gall-bladder electrolyte transport. This conclusion must, however, remain
in doubt in view of the absence of evidence to substantiate gall bladder
evacuation in the affected child.
NEUROENDOCRINE TUMOUR SYNDROMES
Abnormalities of gall-bladder function have been reported in the Verner
Morrison syndrome (pancreatic cholera or WDHA syndrome). Patients
with this syndrome have raised circulating VIP concentrations and large
atonic gall bladders98 99 containing a dilute bile rich in bicarbonate.°
These changes may be accounted for by a relaxant effect of VIP on
gall-bladder muscle, by its ability to antagonise the contractile effects of
cholecystokinin,'10-1'05 by its effects on gall-bladder fluid transport similar
to those described above for 1uinea pig and cat, and by changes in the
composition of hepatic bile. 16 Though changes in bile composition
have not yet been reported in association with hypersecretion of other
gastrointestinal hormones it is of interest that cholelithiasis is a feature of
the somatostatinoma syndrome.108 Somatostatin has been reported to
reverse cholecystokinin induced gall-bladder contraction in the dog in
vivo109 but not in vitro. 105 It is also able to reverse the inhibitory effect of
VIP and secretin on gall-bladder fluid transport.61 Whether or not the
susceptibility to cholelithiasis results from reduced postprandial gall
bladder evacuation or from impaired regulation of gall-bladder fluid
transport remains to be determined.
GALL-BLADDER FLUID TRANSPORT IN CHOLECYSTITIS
The absorptive function of the gall bladder in gall-stone disease in man is
known only from visualisation at cholecystography or from studies in vitro.
The general consensus from radiological studies is that the gall bladder can
be visualised in chronic but not acute cholecystitis. In a study of transport
by human gall bladders excised at cholecystectomy absorptive function
correlated with histological and clinical findings."1' Patients with more
marked clinical findings were found to have more extensive histological
changes and poor absorptive function in the gall bladder. In experimental
cholelithiasis in the rabbit Kyd and Bouchier,112 however, found no
difference in the rate of water absorption between stone forming and
588
Wood and Svanvik
control gall bladders. Lee in a subsequent study in isolated guinea pig and
rabbit gall bladder has reported an enhanced water absorption per unit
gall-bladder weight during lithogenesis."13 This in vitro function may not be
comparable with the ability of the gall bladder to absorb water and
electrolytes in vivo where blood supply, lymphatic drainage and nervous
and humoral factors influence its function.
In a recent study" 4 fluid transport by the gall bladder was studied in
experimental cholecystitis in the cat. Cholecystitis was induced by
implanting human gall stones into the cat gall bladders. Three months later
the concentrating function of the gall bladder was studied in vivo in the
anaesthetised animal. It was found that in animals with a patent cystic duct
the concentrating function of the gall bladder was intact despite a slight or
moderate inflammation of the mucosa. In contrast, animals with gall-stone
induced cystic duct obstruction whose gall-bladder mucosa was markedly
inflamed continuously secreted fluid into the gall-bladder lumen, forming a
hydrops. Indomethacin, a prostaglandin synthetase inhibitor, promptly
reversed this fluid secretion to an absorption suggesting that endogenous
prostaglandin formation may be responsible for the observed fluid
transport change. In a recent study in dogs115 it was found that obstruction
of the gall bladder in combination with infection of its contents induced a
continuous fluid secretion into its lumen that was sustained for several
days. This secretion was markedly reduced by indomethacin further
supporting the role of prostaglandins in secretion by the inflamed gall
bladder.
A factor considered important in the pathophysiology of cholecystitis is
formation of lysolecithin by hydrolysis of phospholipids in the gall
bladder."16 It has recently been reported' "9 that addition of lysolethicin to
an electrolyte solution in the gall-bladder lumen at a concentration
comparable with that found in the bile of patients with acute
cholecystitis"8S reversed the direction of transport to a net secretion. This
fluid secretion was abolished by indomethacin suggesting that at least part
of the change in fluid transport may result from endogenous prostaglandin
formation.
In acute cholecystitis the gall-bladder neck is often obstructed by a gall
stone. A reversal of the direction of fluid transport across the gall-bladder
mucosa to a net secretion into the lumen will cause distension of the
obstructed gall bladder. Distension has recently been reported to stimulate
prostaglandins synthesis by the gall-bladder wall.'19 The clinical course of
acute cholecystitis with necrosis and gall-bladder perforation can be
explained by these changes. 120 This hypothesis is further supported by the
finding that the intraluminal pressure in the gall bladder in acute
cholecystitis is markedly raised, sometimes to values exceeding 90 mm
Hg. 121 122
J R WOOD AND J SVANVIK
Department of Surgery
Kings College Hospital Medical School
University of London, London
and
Department of Surgery I
University of Goteborg
Goteborg, Sweden
Received for publication 2 September 1982
589
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Gall-bladder water and electrolyte
transport and its regulation.
J R Wood and J Svanvik
Gut 1983 24: 579-593
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Gall-bladder water and electrolyte transport and its regulation

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