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Otilonium bromide (OB) is a spasmolytic agent that blocks L-Type Calcium channels in human colonic smooth muscle.

Gallstones are a major public health problem in all developed countries. Many epidemiological studies have been performed with the aim of establishing gallstone prevalence and incidence rates, and of defining risk factors, amenable to prevention. Cholesterol gallstones constitute more than 80% of stones in the Western world. The data usually employed in assessing gallstone prevalence were derived until recently from selected series of patients (necropsies, surgery, etc), which may not represent the general population. Suffice to say that the reported 0% prevalence of gallstones in the Masai population was deduced from surgical experience in that area, which is far from being an ideal way to collect epidemiological data. Necropsy studies are subject to selection bias, which can be reduced by adjusting the data by standardisation. Necropsy studies have shown that, even after standardisation for age and sex, there are major differences between different countries (table 1). The available necropsy data, scrutinising longer intervals of time, decades1 2 or even a century,3 have revealed a trend of increasing gallstone prevalence. View this table: Table 1 Age standardised necropsy prevalence of gallstones (see p 228 for list of references) Cholecystectomy rates, which fluctuate considerably (as much as fivefold) between countries and periods of time, have little relation to the prevalence rates. Oral cholecystography has been used by several researchers to assess gallstone prevalence, but no satisfactory evaluation on the prevalence of silent gallstones in the population was achieved. Currently, most studies have used real time ultrasonography as a screening method in randomly selected populations. Ultrasonography does not only allow the assessment of prevalence, but it is also suitable for follow up in order to establish gallstone incidence and to define risk factors for gallstone disease. Accurate data for local gallstone prevalence and incidence rates are not yet available for every country. The largest number of …

Recently the common adiponutrin (PNPLA3) polymorphism p.I148M has been identified as a genetic determinant of severe forms of non-alcoholic fatty liver disease and alcoholic liver disease. Additionally, insulin resistance - linked to the development of non-alcoholic steatohepatitis - increases the risk of developing gallstones. Here we assessed whether the PNPLA3 p.I148M (c.444 C-G) polymorphism affects glucose and lipid levels and increases gallstone risk. We analysed 229 individuals with gallstones from 108 families (age 24-80 years, BMI 17-55 kg/m(2)) and 258 gallstone-free controls (age 20-70 years, BMI 14-43 kg/m(2)). Fasting glucose, triglyceride and cholesterol serum levels were determined. The p.I148M polymorphism was genotyped using a PCR-based assay with 5'-nuclease and fluorescence detection. Case-control association tests and nonparametric linkage (NPL) analysis in sib-pairs were performed. Individuals carrying the [GG] genotype had significantly (P0.0001) higher median fasting glucose levels as compared to [GC] and [CC] carriers. After adjustment for multiple testing, we detected a trend for an association between triglyceride levels and variant adiponutrin in gallstone patients (P=0.032), and gallstone cases carrying the genotype [CC] presented with significantly higher triglyceride levels than the corresponding controls (P0.003). No significant effects on cholesterol metabolism were detected. Neither genotype distributions nor NPL scores provided evidence for association or linkage between the PNPLA3 variant and gallstones. In conclusion, homozygous carriers of the PNPLA3 risk allele display higher fasting glucose. Although this adiponutrin variant may affect triglyceride homeostasis, it does not increase the risk of cholelithiasis.

Alpha1-antitrypsin (α1AT) deficiency caused by Z allele homozygosity represents a well-established risk factor for hepatocellular carcinoma. Previous studies have also implicated α1AT Z heterozygosity in cholangiocarcinogenesis.To assess the 'common' Z and S alleles as well as the promoter variant rs8004738 for association with cholangiocarcinoma.We genotyped 182 Caucasian patients and 350 controls for rs28929474 (Z), rs17580 (S) and the variant rs8004738. Exploratory analyses were performed in relation to gender and cholangiocarcinoma localisation.rs28929474 was significantly enriched in the cholangiocarcinoma group (4.1 vs. 1.7%; OR 2.46, 95% CI 1.14-5.32; Bonferroni corrected p(c) = 0.036), reinforced by Armitage trend testing (OR 2.53; p(c) = 0.032). The rs8004738 (promoter) minor allele tended to be overrepresented in Z heterozygotes (30.0 vs. 16.7%: P = 0.13). Exploratory data analyses suggested a high genetic risk for extrahepatic tumour localisation (OR 3.0; p(c) = 0.016) and potentially female Z allele carriers (OR 3.37; unadjusted P = 0.022, p(c) = 0.088).These data point to a novel role of α1AT Z heterozygosity as a potential genetic susceptibility factor for cholangiocarcinoma formation and suggest a contribution of aberrant α1AT function in biliary carcinogenesis. However, given the overall low rs28929474 minor allele frequency, larger studies are warranted to confirm and extend our findings.

OBJECTIVE--To assess the management of patients with coeliac disease in relation to a change in diagnostic method from jejunal suction biopsy to endoscopic biopsy. DESIGN--16 item questionnaire survey of consultant members of the British Society of Gastroenterology. SUBJECTS--359 consultant physician and gastroenterologist members of the society. MAIN MEASURES--Type of routine biopsy; repeat biopsy after gluten withdrawal; gluten rechallenge; follow up measurements; screening for malignancy; and methods of follow up, including special clinics. RESULTS--270(70%) members replied; 216(80%) diagnosed coeliac disease routinely by endoscopic duodenal biopsy, 30(11%) by jejunal capsule biopsy, and the remainder by either method. Only 156(58%) repeated the biopsy after gluten withdrawal, though more did so for duodenal than jejunal biopsies (134/216, 62% v 13/30, 43%; p < 0.02). Follow up biopsies featured more duodenal than jejunal biopsies (133/156, 82% v 23/156, 15%; p < 0.02). Regular follow up included assessments of weight (259, 96%) and full blood count (238, 88%) but limited assessment of serum B-12 and folate (120, 44%) and calcium (105, 39%) concentrations. Routine screening for malignancy is not performed, and there are few specialist clinics. 171(63%) respondents thought that patients should be followed up by a hospital specialist and 58(21%) by family doctors. CONCLUSIONS--The practice of diagnosing coeliac disease varies appreciably from that in many standard texts. Many patients could be effectively cared for by their family doctor. IMPLICATIONS--The British Society of Gastroenterology should support such management by family doctors by providing clear guidelines for them.

Personality changes have been reported in chronic constipation. Hostility is an important personality factor involved in psychosomatic disorders. The aim of this study was to investigate hostility in patients with chronic constipation. Sixty subjects with chronic constipation (24 males, 36 females, mean age 44.5 years) were investigated with the hostility scale of the Minnesota Multiphasic Inventory. The patients were divided in four groups according to their symptoms: functional chronic constipation (Group I, n = 18), irritable bowel syndrome expressed as chronic constipation and abdominal pain (Group II, n = 21), irritable bowel syndrome expressed as chronic constipation, abdominal pain and bloating (Group III, n = 13) and irritable bowel syndrome expressed as chronic constipation alternating with episodes of diarrhoea (Group IV, n = 8). Twenty-five clinically healthy subjects were investigated as controls. Hostility was as follows (mean +/- SD): 68 +/- 9 in group I, 62 +/- 12 in group II, 70 +/- 14 in group III, 56 +/- 12 in group IV and 40 +/- 12 in controls. The scores were significantly higher in all groups of patients with constipation versus controls (p0.01;0.001;0.001;0.02, respectively). These data suggest that hostility is increased in patients with chronic constipation. It is rather a feature of the functional bowel disorders than of constipation, as symptom, only.

BACKGROUND AND AIM: An impaired contractility has been suggested as a contributor to the increased incidence of gallstones in liver cirrhosis, but the few studies on gall bladder emptying in cirrhotics offered contradictory results. Ingestion of a meal triggers the physiological pathway of gall bladder emptying; therefore, it was decided to analyse postprandial kinetics by investigating simultaneously the rates of gastric and gall bladder emptying of a mixed meal in patients with liver cirrhosis. METHODS: Gastric and gall bladder emptying were measured using ultrasound techniques after a solid-liquid meal (14 g fat, 425 kcal) in 24 patients with liver cirrhosis and in 12 controls. None of the subjects had gall bladder disease. Sequential changes in cross sectional area of the gastric antrum and in gall bladder volume were represented as a monoexponential process after the test meal. Cirrhotic patients were analysed according to the severity of disease (Child classes). The presence of portal gastropathy was assessed by endoscopy. Differences between groups were assessed using the two tailed Student's t test for unpaired observations and the correlations by linear regression (Pearson's coefficient). RESULTS: It was found that gastric emptying after the solid-liquid meal was delayed in cirrhotic patients compared with controls. Gall bladder emptying was significantly diminished in cirrhotic patients: the area under curve was greater in Child A (p = 0.01), Child B (p = 0.04), and Child C (p = 0.014) cirrhotics compared with controls. No correlation was found between the variables of gastric and gall bladder emptying. Gall bladder refilling began earlier in cirrhotics than in controls, before completion of gastric emptying. CONCLUSIONS: These results indicate the lack of coordination between gastric and gall bladder emptying in liver cirrhosis. They also support the hypothesis that diminished gall bladder contractility might contribute to the increased gallstone formation in liver cirrhosis.

690 PATATIN-LIKE PHOSPHOLIPASE-3 (PNPLA3) VARIATION AND BILIARY TRACT CANCER RISK V. Zimmer, A. Hoblinger, F. Mihalache, M. Krawczyk, F. Grunhage, M. Acalovschi, F. Lammert. Department of Medicine II, Saarland University Medical Center, Homburg, Department of Medicine I, University of Bonn, Bonn, Germany; Department of Medicine III, University Iuliu Hatieganu, Cluj-Napoca, Romania E-mail: vincent.zimmer@uks.eu

The present study retrospectively analyses all the necropsies (5, 112) performed in the two departments of pathology of a large Romanian town (Cluj-Napoca) during a ten-year interval (1983-1992) in order to estimate the prevalence of hepatocellular carcinoma (HCC). To evaluate the time trends of the association of HCC with liver cirrhosis, all cirrhotic subjects necropsied during two consecutive ten years intervals in one of the departments of pathology (Third Medical Clinic) were analysed. The prevalence of HCC was 8/100,000, with a derived incidence of 1.6/100,000 population/year. HCC was more frequent in males, and it occurred more frequently in cirrhotics (13.8%) than in noncirrhotics (0.6%) (p0.0001). The trends in the incidence of HCC in liver cirrhosis were evaluated for the 258 cirrhotic subjects necropsied during two ten year periods (1973-1982 and 1983-1992) in the Third Medical Clinic. HCC was found in cirrhotics older than 40 years, in proportions between 14 and 25% for the different age groups. There was an increasing tendency of HCC incidence in cirrhotic subjects over the last 20 years, significant for the 70-79 years age group. These data indicate a low incidence of HCC in our geographic area and suggest an increasing trend of the HCC association to liver cirrhosis over the last 20 years, more obvious in the advanced ages.

Hepatitis C viral infection is one of the major public health problems, with a global prevalence of 2.35%. It is estimated that approximately 160 million people have been infected with HCV. Metabolic bone disease (often known as hepatic osteodystrophy) is a common complication of long-standing liver disease (affects 1255% of patients), and has an important effect on life as it causes fractures with immobilization. 85 patients with chronic HCV infection and 120 healthy controls were included in the study. Subgroups were defined on the basis of age, gender, menopausal status, alcohol intake, hormonal therapy, Metavir score, and serum viral load. Bone mineral density at the level of lumbar spine was evaluated using DEXA equipment: the WHO classification of osteoporosis was used. Diagnosis of chronic HCV liver disease was based on clinical, laboratory, imaging and invasive (liver biopsy) evidence. Student’s t, chi-square, Mann-Whitney tests, and logistic regression were used to assess the risk factors for osteoporosis in these patients. Prevalence of osteoporosis in patients versus controls was higher both in women (48.9% versus 37.2%) (p=0.003) and men (13% versus 8%) (p=0,645). Low BMD was significantly associated with patients’ age (p 5 years, as compared with those recently diagnosed (78.18% versus 11.36%, p

In order to assess gall-bladder (GB) motility in obese patients, we measured by ultrasound the GB fasting volume (FV) in 45 women (23 obese, 22 controls) and 43 men (21 obese, 22 controls). The FV was larger in obese women (45.9 +/- 21.6 cm3) than in controls (26.6 +/- 10.7 cm3) (P less than 0.001), and also in obese men (39.2 +/- 20.2 vs. 23.8 +/- 9.9 cm3) (P less than 0.01). In obese women, GB FV correlated with relative body weight. No correlation was found between GB volume and age in obese subjects. In controls, but not in obese subjects, the GB ejection fraction was significantly greater in men (65.3 +/- 19.9%) than in women (51.3 +/- 9.0%) (P less than 0.02). Gall-bladder contraction was not decreased in obese subjects vs. controls, suggesting that GB hypocontractility is not a lithogenic risk factor in obesity. The observation that GB emptying does not correlate with body weight represents another argument that obesity does not impair GB contraction.

We conducted a longitudinal follow-up of 72 patients with liver cirrhosis (LC) in order to assess gallstone (GS) incidence. The period of survey was 24.5 +/- 12.2 months. Patients were divided into two groups: group I--26 patients with ascites at the start or appearing during follow-up, and Group II--46 patients with compensated LC (no ascites) throughout the survey. During follow-up, 12 of 72 (16.6%) patients developed GS. The global cumulative incidence of GS was 5.5 cases/100 people/year. Age and sex had no influence on the incidence of GS in LC; neither had etiology or cirrhosis. On the contrary, the study revealed a significant increase in the incidence of GS in decompensated cirrhosis. In group I patients, GS appeared more frequently (34.6%) than in group II patients (6.5%) (chi 2 9.479; p less than 0.002). The cumulative incidence of GS was five times higher in decompensated versus compensated LC.

A comparative study of the mineralogical-structural characteristics and chemical composition of gallstones was performed on stone samples removed intraoperatively from the gallbladders of 12 patients. The study included all the types of gallstones. Their chemical components determined were: bilirubin, cholesterol, phospholipids, calcium, proteins. The stones were examined physically (size, number, shape, color) and the radial or concentric disposition of the layers was estimated on cross-sections. Thin sections (2 X 10(-2)mm) were obtained and examined by polarizing microscope in order to observe the inner structural characteristics. The crystallographic analysis of all the types of stones studied is reported. In all the samples, a perfect concordance was found between the mineralogical structure and the chemical composition of the gallstones. The results obtained are valuable premises for further research in the formation of stones, since a mineralogical study offers the possibility to estimate variations of crystal aggregation, according to the local changes of the gallbladder (inflammation, bacterial growth, pH, etc.).

The study evaluates the impact of advances in biliary imaging techniques on the accuracy and rapidity of diagnosis in patients with obstructive jaundice. Two series of patients hospitalized at an interval of 5 years in the same clinic were prospectively analyzed. In both series, the results of ultrasonography (US) and percutaneous transhepatic cholangiography (PTC) were compared with the intraoperative findings. The performances of US in the assessment of ductal dilatation and choledocholithiasis significantly improved during this period. The fine-needle biopsies taken from the solid masses in liver or pancreatic parenchyma under US guidance in the second series of patients contributed to the greater proportion of correct preoperative diagnoses in this group. The number of PTC investigations increased in the second group (p less than 0.001) given the clinicians' confidence in the safety and easy performance of this method. Using both methods, the etiology of biliary obstruction was correctly diagnosed preoperatively in 85.2 per cent of the second series of patients, significantly more frequently than in the first series of patients (62.7 per cent) (p less than 0.05). The mean period in hospital necessary for the diagnosis decreased during the period analyzed from 15.4 +/- 10.8 days to 10.2 +/- 7.8 days (p less than 0.05), a fact with direct impact on the course of disease, and also on the hospital costs.

A sonographic prospective study of the prevalence of gallstones was performed in 140 patients with liver cirrhosis and in 140 controls. Gallstones were found more often in cirrhotic patients (29.2%) than in controls (13.6%) (p less than 0.01). Their prevalence increased with age. The ratio of women to men in cirrhotics was the same as in the general population, with a higher prevalence in women. The prevalence of gallstones increased in decompensated liver disease. There was a significantly higher prevalence of both hypersplenism and hemolysis in cirrhosis. No difference was found in gallstone prevalence in relation to cirrhosis etiology. This prospective study confirms, by means of sonography, the high prevalence of cholelithiasis in liver cirrhosis, and extends the previous data about the lithogenic risk factors in this disease.

In order to define the relationship between cholesterolosis (COL) and cholesterol gallstone disease (CGD), risk factors were comparatively investigated in a great number of patients. Sex, age and metabolic risk factors were the same for both diseases, but gallbladder anomalies and neuroendocrine disturbances were more often associated with COL. The lipid composition of the gallbladder bile was determined in patients with COL. The bile acid decrease and the increase of cholesterol molar concentration (moles %) were found, similar to those known in CGD. The similarity of risk factors and of bile lithogenicity, as well as the frequent association of COL and CGD suggest a pathogenic relationship of both diseases. Local morphological changes in conditions of high biliary cholesterol levels may be responsible for the intraparietal precipitation of cholesterol in COL. Thus, COL seem to be a peculiar variant of CGD and its classification into the heterogeneous group of cholecystoses is at present questionable.

The prevalence of cholelithiasis in liver cirrhosis was analyzed on 1320 consecutive necropsies which included 245 subjects with gallstones and 133 with liver cirrhosis. Gallstones were found in 24.8% of the cirrhotics, a prevalence significantly higher than in noncirrhotic subjects (17.8%) (p less than 0.05), and were more frequent in cirrhosis for all age-groups. The mean age of death was lower in cirrhotic than in noncirrhotic subjects (p less than 0.05). It was also lower, but without statistical significance, in cirrhotics without gallstones than in cirrhotics having gallstones. The ratio between lithiasic women and men was 0.8/1 in liver cirrhosis, as compared to 1.6/1 in noncirrhotic subjects. The proportion of pigment stones was significantly increased in liver cirrhosis (47.5%) (p less than 0.02). Chronic hemolysis secondary to hypersplenism, a know lithogenic factor in liver cirrhosis, might account for the predominance of pigment stones in this disease. Other lithogenic factors could be hyperestrogenism, changes in the proportion of biliary lipids etc. Complications of gallstones occurred less frequently in cirrhotic than in noncirrhotic patients, but complications of cholecystectomy represented the cause of death in 27.2% of cirrhotics as compared to 14.0% of noncirrhotic patients (p less than 0.02). These observations argue for a conservative, non-surgical attitude towards silent or uncomplicated gallstones in cirrhotic patient.