The MUTYH hotspot mutations p.G396D and p.Y179C do not cause substantial genetic susceptibility to biliary cancer.

Inflammation-associated oxidative stress and DNA damage are involved in malignant transformation of cholangiocytes. Defective DNA repair mechanisms may predispose to cholangiocarcinoma (CCA) formation, and an elevated CCA risk for MutY human homologue (MUTYH) germline mutation carriers has been proposed previously. The aim of this study was to re-evaluate the MUTYH hotspot mutations p.Y179C (rs34612342) and p.G396D (rs36053993) as genetic susceptibility factors in a large CCA cohort. The study population consisted of 219 Caucasian CCA patients (66.2 ± 11.9 years, 130 males, 89 females; 43 intrahepatic and 176 extrahepatic tumours; tissue diagnosis in 77.6 %) and 355 healthy controls (61.0 ± 11.0 years; 158 males, 197 females). MUTYH hotspot variants were genotyped using TaqMan assays. Four CCA patients were monoallelic mutation carriers (3 p.G396D; 1 p.Y179C) whereas 6 control subjects were heterozygotes (5 p.G396D; 1 p.Y179C). None of the patients carried a biallelic hotspot mutation. The observed allele frequencies did not differ significantly between cases and controls (p > 0.05) and association tests did not provide evidence for an involvement of p.Y179C (OR 1.6 [95 % CI 0.1-26.0]) or p.G396D (OR 1.0 [95 % CI 0.2-4.1]) in the susceptibility to CCA. Power analysis identified a sufficient power only for large effect sizes (>90 % for OR > 5.8 for p.G396D and OR > 18.5 for p.Y179C). Monoallelic MUTYH hotspot mutations do not act as major genetic susceptibility factors causing a substantial CCA risk in the Caucasian population. Due to the low statistical power for the identification of small effect sizes, much larger studies will be needed to detect such effects of minor clinical significance.

Mortality and need of surgical treatment in acute upper gastrointestinal bleeding: a one year study in a tertiary center with a 24 hours / day-7 days / week endoscopy call. Has anything changed?

BACKGROUND: Acute upper gastrointestinal bleeding, previously often a surgical problem, is now the most common gastroenterological emergency. AIM: To evaluate the current situation in terms of mortality and need of surgery. SUBJECTS AND METHODS: Retrospective non-randomised clinical study performed between 1st January-31st December 2011, at "Professor Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology in Cluj Napoca. 757 patients with upper gastrointestinal bleeding were endoscopically examined within 24 hours from presentation in the emergency unit. Data were collected from admission charts and Hospital Manager programme. Statistical analysis was performed with GraphPad 2004, using the following tests: chi square, Spearman, Kruskall-Wallis, Mann-Whitney, area under receiver operating curve. RESULTS: Non-variceal etiology was predominant, the main cause was bleeding being peptic ulcer. In hospital global mortality was of 10.43%, global rebleeding rate was 12.02%, surgery was performed in 7.66% of patients. Urgent haemostatic surgery was needed in 3.68% of patients with nonvariceal bleeding. The need for surgery correlated with the postendoscopic Rockall score (p=0.0425). In peptic ulcer, the need for surgery was not influenced by time to endoscopy or type of treatment (p=0.1452). Weekend (p=0.996) or night (p=0.5414) admission were not correlated with a higher need for surgery. CONCLUSIONS: Over the last decade, the need for urgent surgery in upper gastrointestinal bleeding has decreased by half, but mortality has remained unchanged.

The common adiponutrin variant p.I148M does not confer gallstone risk but affects fasting glucose and triglyceride levels.

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 (P<0.0001) 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 (P<0.003). 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.

Randomised clinical trial: otilonium bromide improves frequency of abdominal pain, severity of distention and time to relapse in patients with irritable bowel syndrome.

BACKGROUND: Otilonium bromide (OB) is a spasmolytic agent that blocks L-Type Calcium channels in human colonic smooth muscle. AIM: To study the efficacy of OB in symptom control in irritable bowel syndrome (IBS). METHODS: A total of 356 patients (46.16±19years, 71% female) with IBS participated in a double-blind, randomised, parallel placebo-controlled phase IV study. OB (40mg t.d.s.) or placebo was administered for 15weeks, and follow-up was extended 10 additional weeks. RESULTS: Otilonium bromide (n=179) and placebo (n=177) groups had comparable demographics, symptom severity and IBS subtype. Both OB and placebo reduced abdominal pain and IBS symptoms. The effect of OB was significantly greater than placebo in the reduction of weekly frequency of episodes of abdominal pain at the end of treatment period (primary endpoint, -0.90±0.88 vs. -0.65±0.91, P=0.03), reduction of abdominal bloating (-1.2±1.2 vs. -0.9±1.1, P=0.02) and global efficacy by patient assessment (1.3±1.1 vs. 1.0±1.1, P=0.047). Intensity of abdominal pain, proportion of patient responders, safety and quality of life scores were similarly affected by OB and placebo. During follow-up, the therapeutic effect of OB remained greater than placebo in terms of withdrawal rate due to symptom relapse (10% vs. 27%, P=0.009), global efficacy of treatment and relapse-free probability (P=0.038). CONCLUSIONS: This placebo-controlled double-blind study shows that otilonium bromide is safe, well tolerated and superior to placebo in reducing the frequency of abdominal pain, severity of abdominal bloating and protecting from symptom relapse in IBS. These results further confirm that patients with IBS can improve during and following treatment with otilonium bromide.

Heterozygosity for the alpha1-antitrypsin Z allele may confer genetic risk of cholangiocarcinoma.

BACKGROUND: 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. AIM: To assess the 'common' Z and S alleles as well as the promoter variant rs8004738 for association with cholangiocarcinoma. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

[Coumarin-induced necrosis--a rare complication of oral anticoagulant therapy]. / Necroza cumarinica--complicatie rara a terapiei anticoagulante orale.

Coumarin-induced skin necrosis represents a clinical entity that occurs very rarely, with an approximate incidence of 0.01-0.1% at patients following oral anticoagulant therapy. Most of the cases become clinical manifest between the 3rd and 6th of anticoagulant treatment (there were reports of late onset of skin necrosis after 15 years of anticoagulant therapy) and the most involved areas include breast, buttocks and thighs microcirculation-rich areas. Early symptoms include paresthesia and sensation of tension associated with an erythematous flush in the affected area. Lesions are well demarcated, painful, initially erythematous or hemorrhagic, with the onset of skin necrosis in the end stage. Early lesions can be reversible with the discontinuation of anticoagulant therapy, but skin necrosis can reoccur even without any other coumarin based treatment. We report the case of a 55-year-old female who presented with coumarin-induced skin necrosis affecting the right breast and the right deltoid area.

Hepatitis C virus infection is a risk factor for gallstone disease: a prospective hospital-based study of patients with chronic viral C hepatitis.

We evaluated the prevalence and the risk factors for gallstone disease in patients with chronic hepatitis C infection. We investigated 453 consecutively admitted patients with chronic infection with hepatitis C virus (HCV) (cirrhosis excluded) and 879 patients without liver disease (October 2006-April 2007). Gallstone disease was diagnosed if gallstones were present at ultrasonography or if there had been a previous cholecystectomy. Variables evaluated were age, gender, gallstone heredity, body mass index, waist circumference, parity, serum lipids, fatty liver, arterial hypertension, diabetes mellitus and metabolic syndrome (International Diabetes Federation criteria). Informed consent was obtained from all patients. We found that 88 of 453 (19%) patients with chronic HCV hepatitis (age 50.1 +/- 11.7 years) and 153 of 879 (17%) controls (age 60.6 +/- 12.6 years) had gallstone disease (GD). Abdominal obesity (OR = 2.108, 95% CI 1.287-3.452) and steatosis (OR = 3.699, 95% CI 2.277-6.008) were risk factors for GD in HCV patients. Gallstone heredity, dyslipidaemia, type 2 diabetes mellitus and metabolic syndrome increased the risk for GD in controls vs HCV patients. Our study shows that even HCV patients with chronic hepatitis but not cirrhosis have an increased prevalence of gallstones. Compared with controls, gallstones are present in HCV patients at a younger age and are associated with central obesity and liver steatosis, but not with gallstone heredity, dyslipidaemia, diabetes mellitus or metabolic syndrome. Although we could not establish a temporal relationship, the association between HCV infection and gall stone disease is real and appears to be causally linked, at least in predisposed individuals (obese and with liver steatosis).

Gallbladder hyporesponsiveness to an exogenous nitric oxide donor, glyceryl trinitrate, in patients with advanced liver cirrhosis.

OBJECTIVE: An increased production of nitric oxide (NO) in liver cirrhosis has been documented. NO could intervene in regulating gallbladder contraction, as suggested by clinical and experimental studies. Our aim was to investigate the influence of an NO donor on gallbladder motility in cirrhotic patients in relation to the severity of liver cirrhosis. METHODS: The subjects were six controls and 18 patients with liver cirrhosis (six in each Child class). Gallbladder emptying was monitored by ultrasound for 90 min after a mixed meal (14 g fat, 425 kcal). Fasting gallbladder volume, minimal residual volume, ejection fraction, area under emptying curve, and half contraction time of the gallbladder were assessed at 15-min intervals. The patients were evaluated on two consecutive days, with or without perlingual administration of 0.5 mg glyceryl trinitrate (GTN). Statistical analysis was performed by the two-tailed Student's t test and Pearson's correlation coefficient. RESULTS: GTN significantly reduced gallbladder motility in controls and compensated cirrhotics (p < 0.02), but had no effect upon gallbladder emptying in Child class B and C cirrhotics. CONCLUSIONS: Gallbladder hypocontractility in liver cirrhosis is related to the severity of the disease. This study is the first to show that GTN has no effect upon gallbladder motility in advanced liver cirrhosis when administered in doses that induce relaxation in controls and compensated cirrhosis.

Hostility in patients with chronic constipation.

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 (p < 0.01; < 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.

Gastric and gall bladder emptying of a mixed meal are not coordinated in liver cirrhosis--a simultaneous sonographic study.

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.

Risk of asymptomatic and symptomatic gallstones in moderately obese women: a longitudinal follow-up study.

Obesity is a rather documented risk factor for the formation of gallstones (GS) in women. The magnitude of the increased risk and the rates of GS occurrence, however, have not been well quantified, except for two studies on the risk of symptomatic stones in obese women. We analyzed the incidence of GS in 157 moderately obese women (body mass index, 31.4 +/- 3.6 kg/ m2) followed up prospectively by ultrasound for 2-6 yr (mean 3.95 yr). Women with morbid obesity (body mass index > 40 kg/m2) were excluded from the study, as well as patients having diseases with lithogenic risk. All the enrolled women had normal cholecystosonogram results at the beginning of the study. Age, family history of GS or obesity, parity, age of obesity onset, hyperlipoproteinemia type, plasma cholesterol (total, HDL, LDL), and triglycerides were assessed. The Student's t, the Mann-Whitney rank sum and the Fisher's exact tests were used, as well as the multiple logistic regression for the multivariate analysis. During the survey, 16 of 157 women (10.2%) developed GS. GS were asymptomatic in 11 persons (68.8%). The cumulative incidence of both asymptomatic and symptomatic GS was 2.6 cases/100 obese women.year. During the follow-up, most of the detected GS were asymptomatic, and this explains the higher GS incidence rate found compared with that previously calculated for symptomatic GS. The following risk factors were associated with GS formation: age (p = 0.002), family history of GS (p = 0.011), early obesity onset (p = 0.003), and hyperlipoproteinemia type IV (p = 0.011). A high risk class might be thus identified among obese women, offering a more realistic approach for the primary prophylaxis of GS.

Time trends in the incidence of hepatocellular carcinoma in liver cirrhosis. A retrospective necropsy study in a large Romanian town (1973-1992).

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%) (p < 0.0001). 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.

Increasing gallstone prevalence and cholecystectomy rate in a large Romanian town. A necropsy study.

To study whether the increasing prevalence of gallstone disease noted in a 100-year interval in a large Romanian town has continued in recent years, we analyzed all necropsies (5234) performed during 10 years (1983-1992) in Cluj-Napoca. Gallstone disease (GD) was defined as the presence of stones or the absence of the gallbladder due to cholecystectomy. The results obtained were compared to those of the previous 10-year period (1973-1982). We found a significant increase of GD both in men (6.9% to 9.8%) (P < 0.001) and women (17.1% to 21.7%) (P < 0.001). The ratio of women to men with GD decreased as compared to the first time period (1.4/1 vs 1.8/1). The actual age-standardized prevalence of GD was higher than that calculated for the first time period: 7.6% in men (5.0% in 1973-1982) and 16.9% in women (8.4% in 1973-1982) (P < 0.001). The necropsy cholecystectomy rate rose markedly; 42.1% of the GD men and 43.0% of the GD women had undergone operation during their life. The present study indicates a higher prevalence of GD in the Romanian town than previously found. The actual prevalence is comparable with that of other central European countries, but it is less than that found in England, Scotland, or Sweden.

Ultrasonographic study of gall-bladder emptying in obese patients.

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.

Management of coeliac disease: a changing diagnostic approach but what value in follow up?

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.

Incidence of gallstones in liver cirrhosis.

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.