Review article: agents affecting gall-bladder motility – role in treatment and prevention of gallstones
Correspondence to: Dr K.J. van Erpecum, Department of Gastroenterology, University Medical Center, PO Box 85500, 3508 GA Utrecht, the Netherlands.
Various agents may either enhance or impair post-prandial gall-bladder motility, and they are identified in this review. When studying the impact of medication on gall-bladder motility, the effects on interdigestive gall-bladder and intestinal motility should also be taken into account. Patients at high risk of gallstone disease, and patients who are treated chronically with gall-bladder motility inhibiting drugs, may benefit from improved gall-bladder motility using a prokinetic agent. However, there are no long-term studies to prove that such a strategy prevents gallstone formation.
Three factors are considered to be important in cholesterol gallstone formation: bile composition (in particular cholesterol supersaturation and hydrophobic bile salts), factors promoting cholesterol crystallization (e.g. certain biliary proteins) and impaired gall-bladder motility. 1 Recent data suggest that, in addition to post-prandial gall-bladder motility, gall-bladder motility in the interdigestive (i.e. fasting) state may have an important role in gallstone pathogenesis. 2
Cholesterol supersaturation and crystal formation
Cholesterol is a relatively insoluble amphiphile. Although solubility of cholesterol in H2O is extremely limited, in gall-bladder bile relatively large amounts (∼20 × 10−3m) of the sterol can be kept in solution. This significant increase in solubility is explained by incorporation of cholesterol in micelles, together with bile salts and phospholipids (mainly phosphatidylcholine). Supersaturation occurs when either too much cholesterol, or not enough bile salts and phosphatidylcholine, is secreted to allow complete micellar solubilization of all cholesterol in bile. Excessive cholesterol may be solubilized in vesicles (spherical bilayers of cholesterol and phospholipids, without bile salts). Furthermore several proteins are secreted into bile, such as apolipoproteins A1 and A2, anionic polypeptide fraction, aminopeptidase N, α1 acid glycoprotein, mucin, haptoglobin, immunoglobulins, phospholipases A2 and C and others. Based on in vitro studies, several of these proteins may either promote or inhibit crystallization of cholesterol (an essential step in gallstone formation) by stabilizing or destabilizing cholesterol-rich vesicles.
Post-prandial gall-bladder motility
Meal ingestion induces considerable gall-bladder emptying (up to 70–80% of fasting gall-bladder volumes) by releasing the hormone cholecystokinin (CCK) from the upper intestine. Impaired gall-bladder emptying may prolong residence of bile in the gall-bladder, thus allowing more time for nucleation of cholesterol crystals from supersaturated bile. Furthermore, in the case of adequate emptying, cholesterol crystals that have nucleated may be ejected to the duodenum, whereas in the case of impaired gall-bladder emptying, these crystals may aggregate into macroscopic gallstones. Several ultrasonographic studies have shown that gallstone patients may be divided into a group with severely impaired or even absent post-prandial emptying (‘bad contractors') and a group with good post-prandial gall-bladder emptying (‘good contractors'). 3 Patients with good contraction often have increased fasting and residual gall-bladder volumes compared with normal controls. 4 Studies in animal models have shown that, after its absorption by the gall-bladder wall from supersaturated bile, excess cholesterol is incorporated within the sarcolemmal plasma membrane of the gall-bladder smooth muscle cell, with decreased membrane fluidity, impaired contractility and impaired relaxation as a result. 5–6 Although impaired motility could be in many cases secondary to biliary cholesterol supersaturation, it may still facilitate the process of gallstone formation. Gall-bladder motility is often impaired in high risk situations for gallstone formation, such as pregnancy, obesity, diabetes mellitus, gastric surgery, treatment with the somatostatin analogue octreotide, very low calorie dieting and total parenteral nutrition. Prospective studies indicate that impaired gall-bladder motility is also an independent risk factor for gallstone recurrence after extracorporeal shockwave lithotripsy. 7
Gall-bladder motility in the fasting (interdigestive) state and its relation to intestinal motility
Recent data indicate that the intestine might also be involved in the pathogenesis of cholesterol gallstone formation. 2 In gallstone patients, both small intestinal 8 and whole gut 9 transit times are prolonged. Longer intestinal transit probably enhances formation of the hydrophobic bile salt deoxycholate by increasing intestinal residence time of bile salts. Several studies have found a positive correlation between the amount of biliary deoxycholate on the one hand and cholesterol saturation index 8–10 and speed of cholesterol crystallization 10 on the other. In acromegalics, octreotide treatment induces a similar combination of increased intestinal transit times, more biliary deoxycholate, increased biliary cholesterol saturation index and fast crystallization. 11
Deoxycholate could enhance cholesterol crystallization by enhancing intestinal absorption, or biliary secretion of cholesterol, or by destabilizing cholesterol-rich vesicles. Apart from the effects on biliary deoxycholate, another, possibly complementary, link between the intestine and gallstone formation could be the relation between intestinal and gall-bladder motility in the fasting (also called interdigestive) state. Significant periodic gall-bladder emptying occurs during this period (20–30% emptying in the fasting state versus 70–80% emptying after a meal) at 1–2-h intervals, associated with the cycle of the intestinal migrating motor complex (MMC) and with a rise of plasma motilin levels. 12 The MMC, a pattern of cyclic contractile activity displayed in the fasting state by the upper intestinal tract, is characterized by three phases: during phase I, contractile activity is absent; phase II reveals irregular activity; and during phase III there are intense, regular, co-ordinated contractions. In healthy subjects significant gall-bladder emptying and high plasma motilin levels are observed mainly before antral phase III. 12 We found that gallstone patients show a pattern of less frequent MMC cycles, with absent interdigestive gall-bladder emptying and altered motilin release compared with control subjects. 13 A similarly prolonged MMC cycle has been found in the ground squirrel model of gallstone formation. 14 The fasting state, i.e. the night, would seem to be the most vulnerable period for gallstone formation. During this period, biliary cholesterol saturation is highest, due to relatively low bile salt secretion and relatively high cholesterol secretion. There is also a progressive concentration of gall-bladder bile during this period, which is partially counteracted by periodic interdigestive gall-bladder contraction in association with antral phase III of the migrating motor complex of the intestine.
Medications promoting gall-bladder motility
Several medications improve gall-bladder motility, by influencing various pathways ( Table 1). For example, the motilin analogue erythromycin strongly enhances gall-bladder motility, beside its well-known antibiotic activity. Indeed, in animal models erythromycin has been shown to enhance both gall-bladder and intestinal motility, with a concomitant reduction of hydrophobic bile salts such as deoxycholate and a decrease of biliary cholesterol crystallization. 14–15 Similarly in healthy humans, erythromycin, whether administered orally or intravenously, improves gall-bladder motility by decreasing both fasting and post-prandial gall-bladder volumes. 16 Furthermore, in diabetic patients suffering from autonomic neuropathy (a high-risk group for gallstone formation), gall-bladder motility is dramatically improved by oral erythromycin. 17 As mentioned before, a similar decrease of fasting gall-bladder volumes occurs during the interdigestive state in association with a rise of endogenous motilin levels and with antral phase III of the intestinal migrating motor complex. 12 In a recent study by Luiking et al. it was shown that the administration of exogenous motilin could also induce gall-bladder emptying, accompanied by initiation of phase III of the MMC. 18 The effects of erythromycin on gall-bladder motility are maintained after prolonged administration. 16
Table 1. Various agents with stimulating or inhibiting effects on gall-bladder motility
|Erythromycin||+ +||Motilin receptor stimulation|
|Cholestyramine||+||Sequestration intraduodenal bile salts|
|Ursodeoxycholic acid||+/+–||↓ biliary Xol, ↓ inflammation|
|Intravenous CCK||+||CCK receptor stimulation|
|Dietary fat||+||CCK release|
|Intravenous amino acids/fatty acids||+||CCK release|
|Cisapride||+||cholinergic effect, ↑ intestinal motility|
|NSAIDs||+||Alteration cyclo-oxygenase pathway|
|Somatostatin||––||Inhibition of CCK release|
|NO donors||–||smooth muscle relaxation|
|Calcium antagonists||–||↓ Ca2+-influx, ↓ smooth muscle contractility |
|Progesterone||–||↓ smooth muscle contractility|
|Loperamide||–||↓ intestinal/gall-bladder motility|
|Hyperinsulinaemia||–||↓ cholinergic tone?|
|Spasmolytics||–||↓ smooth muscle contractility|
|Calcitonin/CGRP||–||↓ smooth muscle tone? antagonizing CCK?|
In normal subjects, acute administration at low doses (4–8 g) of the bile salt sequestrant cholestyramine (Questran®, Bristol-Myers Squibb, Woerden, The Netherlands) leads to strong gall-bladder contraction, comparable with meal administration. Interruption of the usual negative feedback by intraduodenal bile salts on hormones such as CCK or motilin is probably the mechanism of this effect. 19 Short-term cholestyramine also improves post-prandial gall-bladder emptying in good and, to a lesser extent, bad contractor gallstone patients. Nevertheless, adaptive responses during prolonged cholestyramine lead to strong decreases of the beneficial effects of the resin. 20 Therefore, it is doubtful whether cholestyramine or similar agents that bind intraduodenal bile salts could be used as prokinetics during long-term treatment.
The effects of therapy with the hydrophilic bile salt ursodeoxycholate on gall-bladder motility are controversial. There is agreement that fasting gall-bladder volumes increase. 21–22 Ursodeoxycholic acid has also been reported to increase minimal post-prandial volumes in some, 22 but not in all, 21 studies. We recently found that in vitro contractility upon CCK- or acetylcholine-induced stimulation of gall-bladder muscle strips obtained during elective cholecystectomy from cholesterol stone patients was better in the case of pre-treatment with ursodeoxycholic acid during 3 weeks before surgery than in untreated gallstone patients. 23 A possible explanation is that ursodeoxycholic acid decreases the cholesterol saturation index (CSI) to unsaturated levels and thus abolishes cholesterol absorption by the gall-bladder wall and incorporation of the sterol in the smooth muscle sarcolemmal plasma membrane. The latter event appears to be a reversible phenomenon, at least in in vitro studies. 24
In patients on parenteral nutrition, daily intravenous injections of CCK, 25 triacylglycerols 26 or amino acids 26 lead to strong gall-bladder contraction, similar in magnitude to meal ingestion. In overweight patients on very low calorie diets, inclusion of small amounts of fat in the diet 27 restores normal gall-bladder motility and avoids the high risk of gallstone formation under these circumstances. Cisapride has been shown to improve gall-bladder and intestinal motility in an animal model 28 and in diabetics (a high-risk group for gallstone disease). 29 Non-steroidal anti-inflammatory drugs improve gall-bladder motility, but this beneficial effect appears to be restricted to gallstone patients. 30–31
MEDICATIONS INHIBITING GALL-BLADDER MOTILITY ( Table 1)
Somatostatin and its analogues such as octreotide are often prescribed in patients with neuroendocrine tumours. These drugs abolish post-prandial gall-bladder motility, particularly through their inhibiting effects on post-prandial CCK release. In a previous study, we found that timing of meal ingestion and subcutaneous (s.c.) octreotide may be important in this respect: whereas post-prandial CCK release and gall-bladder emptying are virtually absent in the case of meal ingestion 45 min or 4 h after s.c. injection of the drug, they are partly restored 8 h after octreotide. 32 Therefore, administration of s.c. octreotide 30 min after breakfast instead of before breakfast, as is current practice, would allow significant evacuation from the gall-bladder of cholesterol supersaturated gall-bladder bile in the early morning period. One has to realize, however, that there is also an important inhibiting effect of octreotide on interdigestive gall-bladder and intestinal motility. 33 Although prolonged treatment with octreotide leads to a high frequency of phase III in the intestine, the origin of these phases is always in the duodenum and not in the antrum (in contrast to the normal situation). Only antral phase III is associated with gall-bladder contraction, and there is no gall-bladder contraction in association with duodenal phase III. 12 Recently, the long-acting somatostatin analogue Sandostatin-LAR® (Novartis, Arnhem, The Netherlands) has become available (only one intramuscular injection each month: stable blood levels during this period). We found increased fasting gall-bladder volumes, severely impaired post-prandial CCK release and gall-bladder contraction and a high gallstone incidence (6/7 patients after 8 months) during Sandostatin-LAR®. 34
Other pharmacological agents can inhibit gall-bladder contraction through non-adrenergic, non-cholinergic pathways. Nitric oxide donors, such as glyceryl trinitrate and l-arginine, cause an increase in both fasting and post-prandial gall-bladder volumes, with concomitant gall-bladder bile stasis. 35 Nitroprusside seems to have a comparable effect. 36 Furthermore, calcium channel antagonists like nifedipine and verapamil have been shown to impair gall-bladder contraction in both animal and human studies, with gall-bladder bile stasis as a consequence. 37 Sex steroid hormone receptors have been localized in both animal and human gall-bladder smooth muscle. 38In vitro studies indicate that higher numbers of sex steroid hormone receptors lead to reduced gall-bladder motor responses to CCK. 39 Progesterone rather than oestrogen impairs gall-bladder motility in in vitro studies. 40 Administration of loperamide also inhibits gall-bladder contraction despite increased post-prandial CCK release. 41 Hyperglycaemia decreases gall-bladder motility in both diabetics and control subjects, possibly through resulting hyperinsulinaemia. 42 Lastly, exogenous administration of calcitonin and calcitonin gene-related peptide negatively affect gall-bladder motility in in vitro studies. 43