Impaired gallbladder motility and delayed orocecal transit contribute to pigment gallstone and biliary sludge formation in β-thalassemia major adults

AIM:Gallbladder and gastrointestinal motility defects existin gallstones patients and to a lesser extent in pigmentgallstone patients.To investigated the role of gallbladderand gastrointestinal motility disorders in pigment gallstoneformation in β-thalassemia major.METHODS:Twenty-three patients with β-thalassemiamajor (16 females;age range 18-37 years) and 70 controls(47 females,age range 18-40 years) were studied forgallbladder and gastric emptying (functional ultrasonography),orocecal transit (OCTT,H_2-breath test),autonomicdysfunction (sweat-spot,cardiorespiratory reflex tests),bowel habits,gastrointestinal symptoms and quality of life(all with questionnaires).Gallbladder content (ultrasonography)was examined before and during 8-12 mo follow-up.RESULTS:Gallstones and/or biliary sludge were found in13 (56%) patients.β-thalassemia major patients hadincreased fasting (38.0±4.8mL vs20.3±0.7mL,P=0.0001)and residual (7.9±13mL vs5.1±0.3mL,P=0.002) volumeand slightly slower emptying (24.9±1.7min vs20.1±0.7min,P=0.04) of the gallbladder,together with longer OCTT(132.2±7.8 min vs99.7±2.3 min,P=0.00003) than controls.No differences in gastric emptying and bowel habits werefound.Also,patients had higher dyspepsia (score:6.7±1.2vs 4.9 0.2,P=0.027),greater appetite (P=0.000004)and lower health perception (P=0.00002) than controls.Autonomic dysfunction was diagnosed in 52% of patients(positive tests:76.2% and 66.7% for parasympathetic andsympathetic involvement,respectively).Patients developingsludge during follow-up (38%,2 with prior stones) hadincreased fasting and residual gallbladder volume.CONCLUSION:Adult β-thalassemia major patients havegallbladder dysmotility associated with delayed smallintestinal transit and autonomic dysfunction.These abnormalities apparently contribute together with haemolytichyperbilirubinemia to the pathogenesis of pigment gallstones/sludge in β-thalassemia major.     

Impaired gallbladder motility and delayed orocecal transit contribute to pigment gallstone and biliary sludge formation in β-thalassemia major adults

AIM: Gallbladder and gastrointestinal motility defects exist in gallstones patients and to a lesser extent in pigment gallstone patients. To investigated the role of gallbladder and gastrointestinal motility disorders in pigment gallstone formation in β-thalassemia major.METHODS: Twenty-three patients with β-thalassemia major (16 females; age range 18-37 years) and 70 controls (47 females, age range 18-40 years) were studied for gallbladder and gastric emptying (functional ultrasonography),orocecal transit (OCTT, H2-breath test), autonomic dysfunction (sweat-spot, cardiorespiratory reflex tests),bowel habits, gastrointestinal symptoms and quality of life (all with questionnaires). Gallbladder content (ultrasonography)was examined before and during 8-12 mo follow-up.RESULTS: Gallstones and/or biliary sludge were found in 13 (56%) patients. β-thalassemia major patients had increased fasting (38.0±4.8 mL vs20,3±0.7 mL, P= 0.0001)and residual (7.9±1.3 mL vs5.1±0.3 mL, P= 0.002) volume and slightly slower emptying (24.9±1.7 min vs20.1±0.7 min,P = 0.04) of the gallbladder, together with longer OCTT (132.2±7.8 min vs99.7±2.3 min, P= 0.00003) than controls.No differences in gastric emptying and bowel habits were found. Also, patients had higher dyspepsia (score: 6.7±1.2vs 4.9±0.2, P = 0.027), greater appetite (P = 0.000004)and lower health perception (P = 0.00002) than controls.Autonomic dysfunction was diagnosed in 52% of patients (positive tests: 76.2% and 66.7% for parasympathetic and sympathetic involvement, respectively). Patients developing sludge during follow-up (38%, 2 with prior stones) had increased fasting and residual gallbladder volume.CONCLUSION: Adult β-thalassemia major patients have gallbladder dysmotility associated with delayed small intestinal transit and autonomic dysfunction. These abnormalities apparently contribute together with haemolytic hyperbilirubinemia to the pathogenesis of pigment gallstones/sludge in β-thalassemia major.     

Risk factors associated with gallstone and biliary sludge formation during pregnancy

AIM: To define the risk factors in gallstone and sludge formation, and to investigate the incidence of gallstone and biliary sludge formation during pregnancy in a group of healthy pregnant women. METHODS: Sixty-nine healthy pregnant women in early gestation and 28 nulliparous healthy controls were enrolled. Gallbladder volumes, gallbladder ejection fraction (GBEF), serum triglyceride and cholesterol levels were determined in both groups. In the pregnant group, repeated measurements were performed immediately after delivery and compared with initial levels. Risk factors, which are associated with gallstone and biliary sludge development during pregnancy, were determined by linear regression analysis. RESULTS: No statistically significant difference was observed in the assessed parameters of pregnant women in early gestation and controls (both P > 0.05). In the pregnant group, gallstone and biliary sludge development during pregnancy were detected in 6.3% and 10.9% of cases, respectively. The detected parameters were significantly higher early after delivery than in early gestation, while GBEF was lower (both P < 0.001). Lower GBEF was the most significant factor (P < 0.001) associated with gallstone and sludge formation during pregnancy, while multiple childbirths was the other (P = 0.04). CONCLUSION: Decrease in GBEF is the most significant risk factor for newly developed gallstone and sludge in pregnant women, while multiple childbirths is the other but less important risk factor.     

Effect of misoprostol on postprandial intestinal motility and orocecal transit time in humans

We measured the effect of misoprostol (M), a PGE₁ analog, on duodenojejunal postprandial motor activity and orocecal transit in eight healthy volunteers. Intestinal motility was studied by an intraluminal catheter with three strain gauge transducers connected to a solid-state datalogger, and transit time was measured by a hydrogen breath test. Subjects were studied for two consecutive days and fed twice a day with a similar, 600-kcal meal. Misoprostol (M) at 800, 400, or 200 g or placebo were taken orally before every one of the four meals. Transit time was measured after the morning meal on both days, after ingestion of either 800 g of M or placebo. On four occasions, following M, the normal fed pattern was not established and the migrating motor complex (MMC) was not interrupted by the meal. In all other occasions, when the higher doses of M were given, the first 1–2 hr after the meal revealed a hypoactive bowel. This effect was inconsistently seen following 200 g of M. Orocecals transit time was consistently and significantly shorter after M than placebo: 48.3±9.5 min vs 104.4±4.8 min,P<0.0001. Four subjects had diarrhea during the study. We conclude that misoprostol, particularly at higher doses, has a profound effect on intestinal postprandial motility and results in accelerated transit time. The motility changes induced by M may be responsible, in part, for its effect on transit.A preliminary report of this work was given at the annual meeting of the American Gastroenterological Association, May 1991, and was published as an abstract inGastroenterology 100:496, 1990. This study was supported in part by Searle.     

Changes in gallbladder motility and gallstone formation following laparoscopic gastric banding for morbid obestity.

Morbid obesity is associated with cholesterol gallstone formation, a risk compounded by rapid weight loss. Laparoscopic gastric banding allows for a measured rate of weight loss, but the subsequent risk for developing gallstones is unknown. METHOD: Twenty-six normal-weight volunteers (body mass index [BMI] less than 30) were compared with 14 morbidly obese patients (BMI greater than 40). Gallbladder volumes were measured ultrasonographically, after fasting and following stimulation with intravenous cholecystokinin-octapeptide (CCK-8) RESULTS: Preoperatively, fasting gallbladder volume and residual volume after CCK stimulation were both two times greater in the obese group (P<0.02 versus controls). Per cent gallbladder emptying was not different. Gallbladder refilling was four times higher in the obese patients (P<0.01). By six weeks postoperatively, the obese patients lost 1.4+/-0.1% body weight per week. Gallbladder emptying decreased 18.4% (80.3+/-3.9% to 65.5+/-6.9%; P<0.05); residual volume rose one-third (not significant), and refilling fell 60.5% (0.43+/-0.09 to 0.26+/-0.04 mL/min; P=0.07). Three patients with weight losses of greater than 1.7% per week developed gallstones; gallbladder emptying fell outside the 95 percentile. By six months, weight loss slowed to 0.5+/-0.1% per week; gallbladder motility improved modestly. No further stones developed. CONCLUSION: Rapid weight loss following laparoscopic gastric banding impairs gallbladder emptying and when pronounced, gallstones form by six weeks postoperatively. The accompanying reduction in gallbladder emptying, increased gallbladder residual volume and decreased refilling promote gallbladder stasis and hence stone formation.     

肝硬化患者胆囊运动功能与胆结石形成的关系探讨

大量临床报道表明肝硬化患者并发胆结石的发生率明显高于非肝硬化群体，且肝硬化程度越重，胆结石发生率越高。本实验采用^99mcTc标记二乙基乙酰苯胺亚氨二醋酸（^99mTc-EHIDA）肝胆动态显像方法，系统研究了肝硬化患者胆囊运动功能受掼晴况，以及胆囊运动功能紊乱与胆结石形成之间的关系。     

Impaired biliary cholesterol secretion and decreased gallstone formation in apolipoprotein E-deficient mice fed a high-cholesterol diet

BACKGROUND & AIMS: Because apolipoprotein E (apoE) is a key cholesterol transport molecule involved in the hepatic uptake of chylomicron cholesterol, it may play a critical role in controlling bile cholesterol elimination and cholesterol gallstone formation induced by dietary cholesterol. To test this hypothesis, we studied biliary lipid secretion and gallstone formation in apoE-deficient mice fed cholesterol-rich diets. METHODS: Bile lipid outputs and gallstone sequence events were analyzed in apoE-deficient mice fed a high-cholesterol diet or a lithogenic diet compared with control animals. RESULTS: A high-cholesterol diet increased biliary cholesterol secretion and gallbladder bile cholesterol concentration in wild-type mice; the increase in bile cholesterol secretion was significantly attenuated in apoE-deficient mice. ApoE knockout mice fed a high-cholesterol lithogenic diet had a markedly lower frequency of gallbladder bile cholesterol crystal and gallstone formation than wild-type mice, which was most likely a result of the decreased cholesterol saturation index found in gallbladder bile of apoE-deficient mice. CONCLUSIONS: These results show that apoE expression is an important factor for regulating both biliary secretion of diet-derived cholesterol as well as diet-induced cholesterol gallstone formation in mice.     

Physico-chemical factors predisposing to pigment gallstone formation in liver cirrhosis

Liver cirrhosis is associated with a high prevalence of pigmentary cholelithiasis. The major compound of pigment gallstones is unconjugated bilirubin (UCB) in the form of calcium bilirubinate salts or a black pigment polymer. Most of UCB in bile derives from enzymic or non-enzymic hydrolysis of mono- or diconjugated bilirubin. Changes in the relative ratios between these two bilirubin species have been associated with pigment gallstones. It has also been shown that UCB solubilization in bile depends on its interaction with bile salts. In order to clarify the factors predisposing cirrhotic patients to pigment stone formation, we measured UCB, monoconjugated bilirubin (MCB) and diconjugated bilirubin (DCB) in duodenal bile of 15 patients with cirrhosis, ten patients with chronic active hepatitis (CAH) and ten normal subjects, we also analyzed their relationships with lipids. In cirrhotic patients, the MCB concentration in bile was significantly (p less than 0.05) higher than in normal subjects and was correlated with the severity of the disease. Bile salts and lecithin concentrations were significantly lower in cirrhosis (p less than 0.005 vs. CAH or normals). Cirrhotic patients have a bile salts/UCB molar ratio which is one third that of CAH patients or normal subjects (p less than 0.01). No differences were found between CAH patients and controls in each of the parameters tested. In conclusion, we propose that the very low BS/UCB molar ratio and the very high biliary content in MCB represent two independent physico-chemical factors predisposing cirrhotic patients to pigmentary cholelithiasis.     

Small intestinal bacterial overgrowth and delayed orocecal transit time in patients with cirrhosis and low-grade hepatic encephalopathy

Background

Hepatic encephalopathy (HE) is associated with poor prognosis in cirrhosis. Gut-derived nitrogenous substances play a role in pathogenesis of HE. The present study was conducted to assess small intestinal bacterial overgrowth (SIBO) and prolonged orocecal transit time (OCTT) in cirrhosis and low-grade HE.

Methods

In cross-sectional prospective study, 75 patients were divided into 3 groups: group 1 (no HE, n = 31), group 2 (minimal HE, n = 29), and group 3 (early/grade 1 HE, n = 15). Minimal HE (MHE) was diagnosed when psychometric hepatic encephalopathy score (PHES) was ≤5. Early HE was diagnosed, according to West Haven criteria. All patients underwent glucose hydrogen breath test (GHBT) for SIBO and lactulose hydrogen breath test (LHBT) for OCTT.

Results

A total of 29 patients (38.67 %) had MHE and 15 (20 %) had early HE. Prevalence of MHE in Child–Turcotte–Pugh (CTP) class A, B, and C was 33.3, 38.71, and 45 %, respectively, while SIBO was detected in 26 (34.67 %). Prevalence of SIBO was 12.5 % in CTP class A, 41.94 % in CTP class B, and 50 % in CTP class C. Five (16.13 %) patients in no HE group had SIBO as compared to 14 (48.28 %) in MHE group and 7 (46.67 %) in early HE group (p = 0.018). OCTT was 111.13 ± 13.95 min in patients with no HE as compared to 137.59 ± 14.80 min in patients with MHE and 150 ± 15.12 min in patients with early HE (p < 0.001). OCTT was significantly prolonged in patients with SIBO (145 ± 17.49 min) than in those without SIBO (120.71 ± 18.3 min) (p < 0.001).

Conclusion

SIBO and delayed OCTT are more common with MHE and early HE in patients with cirrhosis.     

Hyperglycemia modulates gallbladder motility and small intestinal transit time in man

The aim of the present study was to investigate the effect of acute hyperglycemia on (1) the intestinal phase of gallbladder contraction induced by the intraduodenal administration of emulsified fat, and (2) the small intestinal transit time measured by the lactulose breath hydrogen test. Six healthy volunteers were studied in random order during normoglycemia and hyperglycemia (blood glucose levels 15 mmol/liter). Gallbladder volumes were measured with ultrasonography. Administration of 1 and 2 g/hr of fat resulted in significant reductions in gallbladder volumes from 24±2 cm³ to 11±1 cm³ (P<0.05) and 8±1 cm³ (P<0.05), respectively during normoglycemia, and from 24±2 cm³ to 21±2 cm³ (P<0.05) and 16±2 cm³, respectively (P<0.05) during hyperglycemia. Compared to normoglycemia, the gallbladder contraction was significantly (P<0.05) reduced during hyperglycemia. No significant differences in CCK secretion were observed between experiments. Small intestinal transit time during hyperglycemia (101±12 min) was significantly (P<0.05) prolonged compared to normoglycemia (57±12 min). During hyperglycemia, basal PP levels and PP secretion in response to intraduodenal fat were significantly (P<0.05) reduced compared to normoglycemia. It is concluded that (1) low doses of intraduodenal emulsified fat result in significant gallbladder contraction and CCK secretion, (2) acute hyperglycemia inhibits intraduodenal fat induced gallbladder contraction, (3) acute hyperglycemia does not affect the intraduodenal fat induced CCK secretion, (4) small intestinal transit is significantly prolonged during acute hyperglycemia, and (5) acute hyperglycemia inhibits basal and stimulated plasma PP secretion, suggesting impaired vagal-cholinergic tone during hyperglycemia.     

Gallbladder mucin and cholesterol and pigment gallstone formation in hamsters

We measured gallbladder mucin production by hamsters fed diets lithogenic for either cholesterol or pigment gallstones. In hamsters on the cholesterol stone diet, gallbladder production of 3H-glucosamine-labeled mucin was elevated two- and seven-fold after 1 and 3 weeks, respectively. After 1 week cholesterol crystals were seen in a mucus gel on the gallbladder surface. In hamsters on the pigment stone diet, gallbladder mucin production was significantly elevated after 1 and 3 weeks. The first precipitation of pigment crystals was in mucus in bile or on the gallbladder surface. Black pigment stones grew by agglomeration of pigment crystals enmeshed in mucus. In conclusion, gallbladder mucin production is increased before cholesterol or pigment stone formation, and the earliest deposition of crystals is in mucus in bile or on the gallbladder surface.