Cholesterol saturation rather than phospholipid/bile salt ratio or protein content affects crystallization sequences in human gallbladder bile.

BACKGROUND: In model biles, cholesterol crystallization (an important factor in gallstone formation) mainly depends on phospholipid/bile salt ratios with characteristic sequences of plate-like (monohydrate) vs. non-plate-like (presumed anhydrous: arcs, needles, tubules, spirals) cholesterol crystals. We now investigate whether the same phenomenon occurs in human bile. METHODS: Appearances of plate-like and non-plate-like cholesterol crystals were determined in filtered bile of 80 cholesterol gallstone patients, and related to biliary lipid and pro-nucleating protein composition. RESULTS: Non-plate-like crystals appeared before plate-like crystals in 9 biles, on the same day in 24 biles, and after plate-like crystals in 31 biles. In 16 biles only plate-like crystals were observed. Crystal sequences did not depend on biliary lipid or protein composition. Cholesterol saturation indexes were higher in biles with than without non-plate-like crystals (150 +/- 6 vs. 125 +/- 12, P = 0.02). In contrast, phospholipid/(bile salt + phospholipid) ratios, bile salt species, phospholipid classes, concentrations of mucin, IgG, IgM, IgA, haptoglobin and alpha-1 acid glycoprotein did not differ. CONCLUSIONS: Cholesterol crystallization sequences in human bile depend on cholesterol saturation index rather than on phospholipid/bile salt ratio.

Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease.

In the formation of cholesterol gallstones, cholesterol hypersecretion into bile causing cholesterol supersaturation and crystallization appears to be the primary factor, with disturbed gallbladder and intestinal motility as secondary factors. Although intestinal uptake mechanisms have not yet been fully elucidated, the HDL receptor scavenger receptor B1 (SRB1) may be involved. Since HDL-cholesterol, both from the intestine and peripheral sources, is the preferred type of cholesterol for biliary secretion, increased HDL transport to the liver can also cause cholesterol hypersecretion in bile. In the hepatocyte, bile formation is regulated by several transmembrane proteins, all belonging to the ABC family. A change in the activity in one of these proteins can have a profound impact on biliary lipid secretion. The bile salt export pump (BSEP or ABCB11) regulates the excretion of bile salts into bile and mutations cause severe cholestasis. The second ABC transporter, ABCB4 (MDR3) regulates the secretion in bile of phosphatidylcholine (PC), while ABCG5/G8 is active in the excretion of cholesterol and sterols into bile. These transporters also facilitate transport of sterols back into the intestinal lumen. Mutations in either of these genes cause sitosterolaemia with increased absorption of plant sterols and cholesterol. Until now, evidence for a genetic background of human gallstone disease is mostly indirect and based on ethnic differences. Only two single gene defects are associated with gallstones. One is an ABCB4 mutation which causes a deficiency in biliary PC secretion and the other is a CYP7A1 mutation, the rate-limiting enzyme in the synthesis of bile salts from cholesterol in the liver. Recently, several common DNA polymorphisms in the ABCG8 gene were discovered that are associated with variations in plasma sterols, which could also influence biliary cholesterol secretion, but there is still a paucity of human studies.

Sphingomyelin protects against apoptosis and hyperproliferation induced by deoxycholate: potential implications for colon cancer.

High fecal deoxycholate levels may promote colonic cancer. Phospholipids protect against bile salt-induced cytotoxicity. We therefore aimed to examine whether the dietary phospholipid sphingomyelin could decrease hyperproliferation induced by deoxycholate. In CaCo2 cells, hyperproliferation (by bromodeoxyuridine assay), phosphorylation state of cellular proteins, and apoptosis with concomitant caspase-3 activity were evaluated after incubation with 50-500 microM deoxycholate, with or without sphingomyelin. At 2 and 4 hr of incubation, deoxycholate induced dose-dependent apoptosis, with concomitant caspase-3 activation. At 16 hr, apoptosis had decreased markedly, but there was dose-dependent hyperproliferation (with changed phosphorylation status of cellular proteins) at this time point. Sphingomyelin dose-dependently reduced deoxycholate-induced apoptosis and hyperproliferation. In conclusion, sphingomyelin reduces deoxycholate-induced hyperproliferation and apoptosis. These findings may have implications for colonic cancer prevention by dietary modification.

Pathways of cholesterol crystallization in model bile and native bile.

Hypersecretion of hepatic cholesterol, chronic supersaturation of bile with cholesterol and rapid precipitation of cholesterol crystals in the gallbladder from cholesterol-enriched vesicles represent the primum movens in cholesterol gallstone formation. Physical-chemical factors and pathways leading to cholesterol crystallization can be investigated in artificial model biles and ex vivo in fresh human bile. Depending on modulatory factors (i.e., lipid concentration, bile salt or phospholipid species, humidity, mucins, etc.), cholesterol can precipitate in several forms (i.e., monohydrate, anhydrous) and habits (i.e., plate-like, needle-like, intermediate arcs, filaments, tubules, spirals). Careful analysis of biliary cholesterol crystals includes biochemical analysis of precipitated crystals, polarizing quantitative light microscopy, and turbidimetric methods. In this paper, recent concepts on cholesterol crystallization in artificial model biles as well as in human bile will be reviewed.

Acute idiopathic pancreatitis: does it really exist or is it a myth?

BACKGROUND: Acute pancreatitis is a severe disease with considerable morbidity and mortality. Gallstones and alcohol abuse are the most frequent causes (75% of patients). Other well-known causes are: hyperlipidemia, hypercalcaemia, abdominal surgery and drugs. In 10%-40% of patients however, no cause is identified after initial diagnostic evaluation: acute idiopathic pancreatitis. Identifying a cause in these patients is important, since the recurrence rate is high. METHODS: A systematic review of the current literature was performed to identify possible causes, diagnoses and treatment options of acute idiopathic pancreatitis. Relevant literature was found via Pubmed. RESULTS: The presence of microlithiasis or biliary sludge is an important cause of acute 'idiopathic' pancreatitis (up to 80% of patients). Microlithiasis and sludge can be detected by transabdominal/endoscopic ultrasonography, ERCP or polarizing light microscopy of bile. Cholecystectomy is the treatment of choice, whereas endoscopic sphincterotomy and ursodeoxycholic acid maintenance therapy are effective alternatives. Sphincter of Oddi dysfunction can be identified as the cause of acute 'idiopathic' pancreatitis in up to 30% of patients. Manometry of Oddi's sphincter is the gold standard for its diagnosis. Endoscopic sphincterotomy prevents recurrence in most patients. Anatomic abnormalities such as major papilla stenosis, pancreas divisum, pancreatic duct strictures and tumours may also cause acute 'idiopathic' pancreatitis. Endoscopic sphincterotomy and surgery are effective treatments. Finally, genetic screening may reveal gene mutations as the cause of acute 'idiopathic' pancreatitis. CONCLUSIONS: Acute 'idiopathic' pancreatitis is a severe disease with a high recurrence rate. Extensive diagnostic investigations may lead to a cause in >90% of patients.

Effects of motilin on human interdigestive gastrointestinal and gallbladder motility, and involvement of 5HT3 receptors.

A plasma motilin peak and a partial gallbladder emptying precede the antral phase III of the migrating motor complex (MMC). To clarify the causal relationship between these factors, we aimed to study the role of motilin in interdigestive gastrointestinal and gallbladder motility simultaneously. In addition, involvement of 5HT3 receptors in the action of motilin was studied. Eight fasting, healthy male volunteers received 13Leu-motilin or 0.9% NaCl i.v. for 30 min, in randomized order on two separate occasions, from 30 min after phase III. Seven of the eight subjects also received the 5HT3 receptor antagonist ondansetron in addition to motilin, on a third occasion. Antroduodenal motility, gallbladder volumes and plasma motilin were measured. The interval between the start of infusion and phase III was 95.0 (57.6-155.7) min for saline, 28.7 (21.0-33.2) min for motilin, and 39.3 (30.7-100.5) min for motilin + ondansetron (P < 0.05). Gallbladder volume decreased by one-third from 10 min after both motilin and motilin + ondansetron infusion (P < 0.05), and returned to baseline with duodenal passage of phase III. In two of the seven subjects phase III was absent after motilin + ondansetron, although gallbladder volume decreased and only refilled during a later spontaneous phase III. We conclude that motilin induces both partial gallbladder emptying and antral phase III. Indeed, although gallbladder emptying clearly precedes antral phase III, ondansetron only prevented phase III in some cases and had no effect on gallbladder emptying. Passage of phase III in the duodenum makes an important contribution to gallbladder refilling.

Regulation of biliary cholesterol secretion is independent of hepatocyte canalicular membrane lipid composition: a study in the diosgenin-fed rat model.

BACKGROUND/AIMS: Phosphatidylcholine (PC) and sphingomyelin (SM) are the major phospholipids on the outer leaflet of the hepatocyte canalicular membrane. Since cholesterol preferentially associates with SM in detergent-resistant microdomains, we hypothesized that canalicular membrane lipid composition could modulate secretion of the sterol into bile. METHODS: Male Wistar rats were fed for 10 days with a control diet with or without the plant sterol diosgenin (1% w/w) to induce biliary cholesterol hypersecretion. Thereafter, lipid compositions and phospholipid molecular species were determined in fistula bile and highly enriched canalicular membrane fractions. RESULTS: Despite four-fold higher biliary cholesterol output in diosgenin-fed rats, no differences were observed between canalicular membranes of diosgenin and control groups with respect to cholesterol/phospholipid ratios (0.58 vs 0.62), phospholipid classes and acyl chain compositions of SMs (16:0 > 24:1 > 24:0 > 22:0 > 18:0 > 23:0 > 20:0 > 24:2), or PCs (mainly diacyl 16:0-18:2, 16:0-20:4, 18:0-20:4, and 18:0-18:2). In contrast to canalicular PCs, bile contained more hydrophilic species (mainly diacyl 16:0-18:2 and 16:0-20:4), without differences between both groups. In vitro resistance of purified canalicular membrane fractions against detergents such as Triton X-100 and taurocholate was also similar in both groups. CONCLUSIONS: Diosgenin-induced biliary cholesterol hypersecretion occurs in the absence of changes of canalicular membrane lipids. Our data therefore do not support a major role of canalicular membrane lipid composition in regulation of biliary cholesterol secretion.

Absence of apolipoprotein E4 genotype, good gallbladder motility and presence of solitary stones delay rather than prevent gallstone recurrence after extracorporeal shock wave lithotripsy.

BACKGROUND/AIMS: Extracorporeal shock wave lithotripsy (ESWL) with adjuvant bile salt dissolution therapy may be successful in selected gallstone patients, but the considerable risk of recurrence is a major drawback. Apolipoprotein E4 genotype and impaired gallbladder motility have been identified as major risk factors for recurrence during short-term follow up. We have now examined their relevance during long-term follow up. METHODS: Eighty-four cholesterol gallstone patients (55 solitary and 29 multiple (two to ten) stones) were followed prospectively up to 10 years after complete stone disappearance. Various potential risk factors for recurrence were evaluated. RESULTS: Gallstone recurrence was found in up to 80% of patients at 10 years follow-up. Absence of the apolipoprotein epsilon4 allele, initial solitary stones, good gallbladder emptying (i.e. minimal postprandial volume < or = 6 ml) and 2-year postdissolution ursodeoxycholic acid prophylaxis (in ten patients) all delayed but did not prevent recurrence. In contrast, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was identified as an independent protective factor, with greatly decreased recurrence (at 10 years: 58 vs 93% in non-NSAID users, P = 0.03). CONCLUSIONS: Non-apolipoprotein E4 genotype, presence of solitary stones and good gallbladder emptying delay rather than prevent recurrence after initially successful ESWL. Regular use of NSAIDs may prevent recurrence.

Cholesterol crystallization in model biles: effects of bile salt and phospholipid species composition.

Cholesterol in human bile is solubilized in micelles by (relatively hydrophobic) bile salts and phosphatidylcholine (unsaturated acyl chains at sn-2 position). Hydrophilic tauroursodeoxycholate, dipalmitoyl phosphatidylcholine, and sphingomyelin all decrease cholesterol crystal-containing zones in the equilibrium ternary phase diagram (van Erpecum, K. J., and M. C. Carey. 1997. Biochim. Biophys. Acta. 1345: 269-282) and thus could be valuable in gallstone prevention. We have now compared crystallization in cholesterol-supersaturated model systems (3.6 g/dl, 37 degrees C) composed of various bile salts as well as egg yolk phosphatidylcholine (unsaturated acyl chains at sn-2 position), dipalmitoyl phosphatidylcholine, or sphingomyelin throughout the phase diagram. At low phospholipid contents [left two-phase (micelle plus crystal-containing) zone], tauroursodeoxycholate, dipalmitoyl phosphatidylcholine, and sphingomyelin all enhanced crystallization. At pathophysiologically relevant intermediate phospholipid contents [central three-phase (micelle plus vesicle plus crystal-containing) zone], tauroursodeoxycholate inhibited, but dipalmitoyl phosphatidylcholine and sphingomyelin enhanced, crystallization. Also, during 10 days of incubation, there was a strong decrease in vesicular cholesterol contents and vesicular cholesterol-to-phospholipid ratios (approximately 1 on day 10), coinciding with a strong increase in crystal mass. At high phospholipid contents [right two-phase (micelle plus vesicle-containing) zone], vesicles were always unsaturated and crystallization did not occur. Strategies aiming to increase amounts of hydrophilic bile salts may be preferable to increasing saturated phospholipids in bile, because the latter may enhance crystallization.

Interdigestive gallbladder emptying, antroduodenal motility, and motilin release patterns are altered in cholesterol gallstone patients.

The role of interdigestive gallbladder emptying in gallstone formation is unknown. In fasting healthy subjects, gallbladder emptying is associated with antral phase III of the migrating motor complex (MMC) and high plasma motilin. Therefore, gallbladder volumes and motilin levels were measured during 13 MMC cycles in 10 cholesterol gallstone patients and compared with 20 MMC cycles in 10 healthy subjects. MMC cycle length was longer in gallstone patients than in healthy subjects (158.2 +/- 17.0 vs 105.5 +/- 10.4 min, respectively; P < 0.05), due to longer phase I (39.8 +/- 5.7 vs 17.2 +/- 3.7 min, respectively; P < 0.05). In contrast to healthy subjects, gallstone patients had no significant fluctuations of gallbladder volume during the MMC cycle, and motilin concentrations were not different in MMC cycles with phase III originating in antrum or duodenum. During MMC cycles with phase III originating in the duodenum, motilin levels were twice as high in gallstone patients as in healthy subjects (P < 0.002). In conclusion, cholesterol gallstone patients have an abnormal MMC and motilin release pattern. Their interdigestive gallbladder emptying is reduced and dissociated from the MMC. These disturbances may contribute to gallstone formation.

Hydrophilic bile salts enhance differential distribution of sphingomyelin and phosphatidylcholine between micellar and vesicular phases: potential implications for their effects in vivo.

BACKGROUND/AIMS: The hepatocyte canalicular membrane outer leaflet contains both phosphatidylcholine (PC) and sphingomyelin (SM). Normally, PC is the exclusive phospholipid in bile. We examined effects of bile salt hydrophobicity on cytotoxicity and on differential SM and PC distribution between detergent-resistant aggregated vesicles (model for detergent-resistant canalicular membrane) and mixed micelles or small unilamellar vesicles (representing lipid phases in bile). METHODS: Aggregated vesicles were obtained by ultracentrifugation of cholesterol-supersaturated model systems containing SM, PC and various bile salts, micelles by ultrafiltration and unilamellar vesicles by dialysis of the supernatant. Erythrocyte hemolysis and lactate dehydrogenase release from CaCo-2 cells upon incubation with various micelles were quantified. RESULTS: Preferential SM distribution and lipid solubilization in aggregated vesicles increased in rank order taurodeoxycholate < taurocholate < tauroursodeoxycholate < taurohyodeoxycholate, with reciprocal PC enrichment in micelles and small unilamellar vesicles. Including small amounts of PC within taurohyodeoxycholate micelles increased cytotoxicity with more erythrocyte hemolysis and LDH release from CaCo-2 cells upon incubation, but decreased cytotoxicity in case of tauroursodeoxycholate micelles. CONCLUSIONS: Hydrophilic but not hydrophobic bile salts preserve integrity of pathophysiologically relevant phosphatidylcholine plus sphingomyelin-containing bilayers. Enhanced biliary phospholipid secretion during taurohyodeoxycholate but not during tauroursodeoxycholate therapy (Hepatology 25 (1997) 1306) may relate to different interactions of these bile salts with phospholipids.

Potential benefits and hazards of physical activity and exercise on the gastrointestinal tract.

This review describes the current state of knowledge on the hazards of exercise and the potential benefits of physical activity on the gastrointestinal tract. In particular, acute strenuous exercise may provoke gastrointestinal symptoms such as heartburn or diarrhoea. A substantial part (20-50%) of endurance athletes are hampered by these symptoms which may deter them from participation in training and competitive events. Nevertheless, these acute symptoms are transient and do not hamper the athlete's health in the long term. The only exception is repeated gastrointestinal bleeding during training and competition, which in the long term may occasionally lead to iron deficiency and anaemia. In contrast, repetitive exercise periods at a relatively low intensity may have protective effects on the gastrointestinal tract. There is strong evidence that physical activity reduces the risk of colon cancer by up to 50%. Less convincing evidence exists for cholelithiasis and constipation. Physical activity may reduce the risk of diverticulosis, gastrointestinal haemorrhage, and inflammatory bowel disease although this cannot be substantiated firmly. Up to now, underlying mechanisms are poorly understood although decreased gastrointestinal blood flow, neuro-immuno-endocrine alterations, increased gastrointestinal motility, and mechanical bouncing during exercise are postulated. Future research on exercise associated digestive processes should give more insight into the relationship between physical activity and the function of the gastrointestinal tract.

Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR.

BACKGROUND: Acromegalic patients treated three times daily with subcutaneous injections of the somatostatin analogue octreotide frequently develop gallstones, due to suppressed cholecystokinin release and impaired gall-bladder emptying. AIM: To elucidate the effects of a new long-acting octreotide formulation (Sandostatin LAR) on gall-bladder emptying, cholecystokinin release and gallstone formation. METHODS: Postprandial gall-bladder and gastric emptying were determined by ultrasonography and cholecystokinin release was measured in seven patients on days 0, 14, 28, and 75 (Sandostatin LAR, 20 mg intramuscularly on days 1, 30, and 60). RESULTS: During treatment, fasting gall-bladder volumes increased from 26.5 +/- 3.2 mL to 61.4 +/- 7.5 mL, but postprandial cholecystokinin release and gall-bladder emptying (from 63.9 +/- 3.8% to 12.3 +/- 3.5%) were severely suppressed. Gallstones formed in six out of seven patients within 8 months of treatment. Gastric emptying did not change during the therapy. CONCLUSIONS: The risk of gallstone formation is greatly increased during Sandostatin LAR. This is probably related to profound suppression of cholecystokinin release and gall-bladder emptying.

Homocysteine in inflammatory bowel disease: a risk factor for thromboembolic complications?

OBJECTIVE: Patients with inflammatory bowel disease (IBD) are at increased risk for thromboembolic events. Hyperhomocysteinemia, which is an established risk factor for arterial as well as venous thrombosis, may be more prevalent in IBD because of vitamin deficiencies. METHODS: In this retrospective study, we studied the concentrations of total homocysteine (tHcy), cobalamin, folate, and pyridoxine in 231 consecutive patients with IBD, of whom 16 patients had a history of venous thrombosis, and nine a history of arterial thrombosis. Age- and gender-matched healthy volunteers served as controls (n = 102). RESULTS: Homocysteine concentrations in patients were higher (12.3 micromol/L [range 4.6-51.3] vs 11.1 micromol/L [range 3.9-27.6], p = 0.001) and hyperhomocysteinemia tended to be more prevalent in patients than in the controls (11.1% vs 5%, p = 0.07). Folate, cobalamin, creatinine, and pyridoxine concentrations were correlated with tHcy. Folate deficiency was infrequently encountered in IBD patients (4.3%). The tHcy concentration in patients with a history of venous or arterial thrombosis was not higher than in patients without a history of thrombosis (12.7 micromol/L [range 4.6-40.1] and 15.2 micromol/L (range 10.5-26.8) vs 12.3 micromol/L [range 10.5-26.8], not significant). Hyperhomocysteinemia was found in 18.8% of the patients with venous thrombosis, 11.1% of the patients with arterial thrombosis, and 10.5% of the patients without thrombosis (not significant). CONCLUSIONS: Hyperhomocysteinemia is a common phenomenon in IBD and correlates with serum folate, cobalamin, creatinine, and pyridoxine concentrations. No correlation between tHcy and a history of venous or arterial thromboembolic complications is found. Hyperhomocysteinemia does not seem to be a major contributory factor in the development of venous or arterial thrombosis in IBD patients.

Review article: in vitro studies of gall-bladder smooth muscle function. Relevance in cholesterol gallstone disease.

The interplay between contraction and relaxation in the gall-bladder muscularis leads to appropriate gall-bladder emptying and refilling during fasting and in the postprandial state in vivo. Several studies in both human and animal models have focused on cellular and molecular events in the gall-bladder wall in health and disease in vitro. Principal methods to study gall-bladder smooth muscle function include receptor binding studies (at the level of plasmamembranes or histological sections), phase contrast microscopy (at the level of isolated smooth muscle cells), and tensiometry (at the level of smooth muscle strips or the whole gall-bladder). At a very early stage, cholesterol gallstone disease is characterized by exposure of the gall-bladder wall to excess of biliary cholesterol and the cytotoxic effect of the bile salt deoxycholate. On a long-term basis, a form of gall-bladder leiomyopathy develops with defects involving the mechanisms of signal transduction at the level of plasmamembranes. The end-stage result is pathological contraction and/or relaxation of smooth musculature, impaired gall-bladder motility and gall-bladder stasis, all key factors in the pathogenesis of biliary cholesterol crystallization and gallstones.

Review article: agents affecting gall-bladder motility--role in treatment and prevention of gallstones.

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.

Sphingomyelin exhibits greatly enhanced protection compared with egg yolk phosphatidylcholine against detergent bile salts.

Inclusion of phosphatidylcholine within bile salt micelles protects against bile salt-induced cytotoxicity. In addition to phosphatidylcholine, bile may contain significant amounts of sphingomyelin, particularly under cholestatic conditions. We compared protective effects of egg yolk phosphatidylcholine (similar to phosphatidylcholine in bile), egg yolk sphingomyelin (mainly 16:0 acyl chains) and dipalmitoyl phosphatidylcholine against taurocholate in complementary in vitro studies. Upon addition of taurocholate-containing micelles to sonicated egg yolk phosphatidylcholine vesicles, subsequent micellization of the vesicular bilayer proved to be retarded when phospholipids had also been included in these micelles in the rank order: egg yolk phosphatidylcholine < dipalmitoyl phosphatidylcholine < sphingomyelin. Hemolysis of erythrocytes and LDH release by CaCo-2 cells after addition of taurocholate micelles were strongly reduced by including small amounts of sphingomyelin or dipalmitoyl phosphatidylcholine in these micelles (PL/(PL + BS) >/= 0.1), whereas egg yolk phosphatidylcholine provided less protection. Amounts of non-phospholipid-associated bile salts (thought to be responsible for cytotoxicity) in egg yolk phosphatidylcholine-containing micelles were significantly higher than in corresponding sphingomyelin- or dipalmitoyl phosphatidylcholine-containing micelles (tested at PL/(PL + BS) ratios 0.1, 0.15, and 0.2). LDH release upon incubation of CaCo-2 cells with taurocholate simple micelles at these so-called "intermixed micellar-vesicular" concentrations was identical to LDH release upon incubation with corresponding taurocholate-phospholipid mixed micelles. In conclusion, we found greatly enhanced protective effects of sphingomyelin and dipalmitoyl phosphatidylcholine compared to egg yolk phosphatidylcholine against bile salt-induced cytotoxicity, related to different amounts of non-phospholipid-associated bile salts. These findings may be relevant for protection against bile salt-induced cytotoxicity in vivo.

Gallbladder motility and cholesterol crystallization in bile from patients with pigment and cholesterol gallstones.

BACKGROUND: Little is known about gallbladder motility in patients with black pigment stones when compared to cholesterol gallstone patients, or about their relationship to biliary composition, crystallization and stone characteristics. DESIGN: Fasting and postprandial gallbladder volumes were studied by ultrasonography in 49 gallstone patients with pigment (n = 14) or cholesterol (n = 35) stones and 30 healthy controls. After cholecystectomy stone composition, gallbladder wall inflammation, cholesterol saturation index and appearance of platelike cholesterol crystals in bile were evaluated in gallstone patients. RESULTS: Fasting gallbladder volume was significantly (P < 0.05) increased in cholesterol stone patients (31.7 +/- 1.9 mL) but not in pigment stone patients (21.9 +/- 3.1 mL), compared to controls (21.0 +/- 1.5 mL). Postprandial emptying was delayed in patients (half-emptying time: 31 +/- 2 min, 35 +/- 3 min, 24 +/- 2 min in cholesterol stone patients, pigment stone patients and controls, respectively, P < 0.05) and incomplete (residual volume: 43.2 +/- 2.7%, 40.0 +/- 4.3%, 15.8 +/- 1.6% min in cholesterol stone patients, pigment stone patients and controls, respectively, P < 0.05). The inflammation of the gallbladder wall was mild or absent in all cases. Biliary cholesterol saturation index was 152.3 +/- 8.5% and 92.9 +/- 4.8% in patients with cholesterol and pigment stones, respectively (P < 0.01). Whereas cholesterol crystals never appeared during 21 days in biles from patients with pigment stones, crystal observation time in patients with cholesterol gallstone was 5 days (median) and was significantly shorter in patients with multiple (4 days) than in patients with solitary (12 days) cholesterol stones (P = 0.0019). CONCLUSIONS: Patients with black pigment stones who do not have excess cholesterol and do not grow cholesterol crystals in bile have decreased gallbladder emptying, although to a lesser extent than patients with cholesterol stones. Thus, gallbladder stasis is likely to put a subset of subjects at risk for the formation of pigment gallstones, and pathogenic mechanisms need to be further investigated.

The effect of acute oral erythromycin on gallbladder motility and on upper gastrointestinal symptoms in gastrectomized patients with and without gallstones: a randomized, placebo-controlled ultrasonographic study.

OBJECTIVE: Gastrectomy might be a risk factor for cholelithiasis and gallbladder stasis might play a major role. We studied fasting and postprandial gallbladder motility with 600 mg oral erythromycin or placebo in gastrectomized patients (with and without gallstones) and controls. METHODS: Seventeen patients operated on for gastric cancer (subtotal gastrectomy: n = 10, total gastrectomy: n = 7) were compared with 20 sex- and body-size matched healthy controls. Subjects randomly received erythromycin or placebo 30 min before the ingestion of a standard 200 ml liquid test meal. Gallbladder volume was estimated by ultrasonography until 120 min after test meal. A visual analog scale monitored GI perception of appetite, satiety, nausea, abdominal fullness and epigastric pain. RESULTS: Gastrectomized patients had increased fasting gallbladder volume (35.9 +/- 3.4 ml versus 21.0 +/- 1.4 ml, p = 0.0005) with faster postmeal emptying (T/2 14.8 +/- 1.1 min versus 23.5 +/- 1.5 min, p = 0.00019) than controls. Six patients developed small and asymptomatic gallstones, which did not influence gallbladder motility. In these patients, fasting gallbladder volume increased with time after surgery (r = +0.82, p = 0.047). Perception of satiety, abdominal fullness, and epigastric pain after ingestion of the test meal were all significantly greater in patients than in controls. Erythromycin significantly enhanced gallbladder emptying during fasting (p = 0.001) and postprandially in both patients and controls (0.002 < p < 0.017) and significantly reduced postmeal satiety and epigastric discomfort in gastrectomized patients. CONCLUSIONS: Increased fasting volume might be a form of stasis, predisposing patients to gallstone formation. Erythromycin improves fasting and postprandial gallbladder emptying and decreases upper GI symptoms in gastrectomized patients.

Determination of actin content in gallbladder tissue and its relevance to normalization of tensiometry data.

OBJECTIVES: To compare the common procedure in tensiometry of normalization of the force (in N) produced by a gallbladder tissue strip to units of stress, with normalization of force to the strip content of contractile protein. DESIGN: A comparison was made in both healthy and in diseased gallbladder tissue strips between two normalization procedures involving anatomical parameters. The contractile response expressed in terms of tissue stress (in N/m2), which entails a normalization to the strip cross-sectional area, was set against normalization to the tissue content of contractile protein (in N/mg actin/g strip wet weight). METHOD: Dose-response curves for acetylcholine (ACh) (10(-8) to 10(-3) M) and sulphated cholecystokinin octapeptide (CCK) (10(-12) to 10(-6) M) were assessed in healthy guinea pig (n = 8) and in diseased human gallbladder tissue strips (n = 28). Assuming a tissue density of 1.05 g/cm3, the strip cross-sectional area was calculated from its weight and length. Actin content in homogenized strips was determined by polyacrylamide gel electrophoresis followed by densitometry. RESULTS: Actin content in human tissue was 19.06 +/- 1.42 mg/g strip wet weight, and 12.84 +/- 0.76 mg/g strip wet weight in guinea pig tissue. No correlation was found between strip cross-sectional area and actin content. In the diseased human tissue, no correlation was found between the inflammation score and either strip cross-sectional area or strip actin content. Maximal force (in mN) exerted in response to either ACh or CCK correlated much more closely in healthy guinea pig gallbladder (r = 0.97) than in diseased human tissue (r = 0.59). Normalization of maximal force to strip cross-sectional area (i.e. to stress) showed considerable more variation (% coefficient of variance) than the normalization to strip actin content in healthy guinea pig tissue, although both strip cross-sectional area and actin content per se showed little variation. Normalization to either parameter did not result in an improved correlation or a decreased variation in the case of diseased human gallbladder tissue. CONCLUSION: Normalization of muscle strip force in diseased tissue is questionable, as the assumptions made for healthy tissue are not valid.