A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population.

BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes. METHODS: We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap). KEY RESULTS: We identified 30 GERD suggestive risk loci (P≤5×10-5 ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds. CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities.

Hepatocellular carcinoma complicating primary sclerosing cholangitis in Crohn's disease. A case report.

The prevalence of primary sclerosing cholangitis (PSC) in Crohn's disease (CD) patients is up to 8.5%. Although cholangiocarcinoma may complicate long-standing PSC in one third of the cases if follow-up is extended long enough, hepatocellular carcinoma (HCC) is a rare complication of PSC. The concomitant presence of PSC, HCC and CD have been reported sporadically. We discuss here a case of association of these three conditions.

Efficacy and safety of oral beclomethasone dipropionate for ileal or ileal-right colon Crohn's disease of mild-to-moderate activity or in remission: Retrospective study.

Although conventional glucocorticosteroids are the main treatments for active Crohn's disease, several problems are associated with steroid dependence and steroid-related adverse events. To assess the efficacy and safety of oral beclomethasone dipropionate (BDP) coated tablets in adults with mild-to-moderate Crohn's disease. Thirty-four patients (age 18-70years) with a diagnosis of Crohn's disease confirmed by conventional criteria (barium enema, clinical criteria, colonoscopy, histology) were retrospectively evaluated in the study. All subjects received a treatment schedule with BDP 5-10mg/day for 24weeks. BDP significantly (p=0.005) reduced mean Crohn's Disease Activity Index (CDAI) score from 169.6 at baseline to 123.2 after 24weeks. Clinical success was evident at 24weeks in 66.7% of patients with initial active disease, and remission was maintained at week 24 in 93.8% of patients with remission at baseline. Overall, female non-smokers had the best response to treatment. BDP was well tolerated and the only adverse events observed were nausea (n=1), facial erythema (n=1) and one patient with raised fasting blood glucose level. These results clearly suggest that oral BDP coated tablets are effective and safe for treatment of mild-to-moderate Crohn's disease of ileal or ileal-right colonic localisation.

CARD15/NOD2 polymorphisms do not explain concordance of Crohn's disease in Swedish monozygotic twins.

BACKGROUND: CARD15/NOD2 polymorphisms are associated with Crohn's disease. There is a high concordance for disease and disease phenotype in monozygotic twin pairs with Crohn's disease. AIM: We studied CARD15/NOD2 polymorphisms in a Swedish, population-based cohort of monozygotic twins with Crohn's disease to assess whether these variants explain disease concordance. SUBJECTS AND METHODS: Twenty-nine monozygotic twin pairs (concordant n=9, discordant n=20) with Crohn's disease and 192 healthy controls were investigated for the CARD15/NOD2 variants Arg702Trp, Gly908Arg and Leu1007fsinsC. RESULTS: CARD15/NOD2 mutations were found in 5/38 (13%) twins with Crohn's disease, corresponding to a total allele frequency of 6.6%. Only 2/9 concordant twin pairs carried any of the variants and the remaining seven were wild type genotype. The total allele frequency was 4.4 times higher (95% confidence interval 1.0-21.5, p=0.06) in concordant twins than in discordant ones, 11.1% versus 2.5%. In healthy controls the total allele frequency was 2.6%. CONCLUSIONS: CARD15/NOD2 polymorphisms contribute but do not alone explain concordance of Crohn's disease in monozygotic twins and, at least in a Swedish population, other polymorphisms are required. The low occurrence of CARD15/NOD2 mutations in the study and other Northern European populations suggests that these variants are of less importance in Northern Europe.

Association between Crohn's disease and Conn's syndrome. A report of two cases.

The natural history of Crohn's disease (CD) is characterised by periods of remission followed by phases of flares. Persistent or intractable diarrhoea may be associated with ileal disease or arise following ileal resection, resulting in potassium depletion. Medical therapy with steroids presents troublesome side-effects (e.g. hypertension). Conn's syndrome, caused by unilateral aldosterone-producing adenoma, is characterised by clinical features including hypokalaemia and hypertension. Thus, CD and Conn's syndrome may have an overlap of manifestations, and up to now, the simultaneous occurrence of these conditions has not been described. We report here 2 cases of association between CD and Conn's syndrome.

Safety and efficacy of azathioprine in the maintenance of ciclosporin-induced remission of ulcerative colitis.

BACKGROUND: It has been shown that azathioprine prolongs the response to ciclosporin of steroid-refractory ulcerative colitis, but no specific data are available concerning its toxicity in this indication. AIM AND METHODS: The charts of 21 patients with steroid-refractory ulcerative colitis who received azathioprine overlapping with a successful ciclosporin course were reviewed for the onset of toxicity. The controls consisted of 48 initial responders to steroids who received azathioprine for steroid-dependence or resistance/toxicity. RESULTS: Two of the 21 patients were withdrawn because of hypersensitivity to azathioprine. The remaining 19 were treated for a median of 18 months together with a median daily steroid dose of 35 mg (10-75 mg) to be tapered off. Toxicity (31%) included leukopenia alone (two cases), cholestasis alone (one case), cholestasis and increased amylase (one case), increased amylase alone (one case), and cutaneous infection (one case). The frequency of withdrawal was 21%. The mean daily steroid doses were reduced from 38 mg to 3.8 mg in the study cohort, and from 25 mg to 8 mg in the controls, among whom toxicity (27%) included four cases each of leukopenia and increased amylase, two cases each of alteration of liver enzymes and infection, and one case of gastric intolerance. Ten of the 48 controls (20%) were withdrawn from the study. CONCLUSION: Azathioprine is as effective and safe in the maintenance of the response of patients with steroid-refractory ulcerative colitis to ciclosporin as it is in the treatment of those who respond to steroids.

[Lithiasis of the gallbladder and biliary ducts: from epidemiology to therapy]. / Litiasi della colecisti e delle vie biliari: dall'epidemiologia alla terapia.

The diagnosis of cholelitiasis, more and more common with the wide diffusion of abdominal ultrasound, is often a surprise for the patient as well as for the physician who is sometimes forced to take a therapeutical decision. In the case of dilatation of the biliary duct, the cholangioRM is assuming an increasingly important role, especially before a therapeutical ERCP. The best therapeutical approach seems to be the surgical ablation in laparoscopy in presence of specific signs and symptoms. Indication to surgical ablation is a symptomatic or complicated cholelithiasis, or the history of obstructive pancreatitis. A preventive cholecystectomy can be useful for precancerous lesions.

Abdominal pain and bowel dysfunction: diagnostic role of intestinal ultrasound.

BACKGROUND: Abdominal pain and irregular bowel habits are common among young people. Irritable bowel syndrome is frequent in the general population and has important economic and social costs. Inflammatory bowel diseases are chronic processes with an acute or indolent onset in young people. Differential clinical diagnosis between irritable bowel syndrome and inflammatory bowel disease can be difficult since symptoms and signs are often non-specific. OBJECTIVE: To evaluate the role of intestinal ultrasound, a non-invasive, simple and cheap diagnostic tool, in the differentiation between organic and functional bowel diseases. METHODS: Abdominal and intestinal ultrasound examinations were performed on 313 consecutive outpatients presenting with abdominal pain and irregular bowel habits lasting more than 3 months. These patients had no symptoms or signs indicative of organic disorders and no previous diagnosis of organic disease. An intestinal wall thickness of more than 7 mm was considered diagnostic for inflammatory bowel disease. Subsequently, we compared the ultrasound results with diagnoses obtained following the traditional criteria (radiological and endoscopic examinations). RESULTS: Intestinal ultrasound for the diagnosis of inflammatory bowel disease showed 74% sensitivity, 98% specificity, a positive predictive value of 92% and a negative predictive value of 92%. CONCLUSIONS: In our experience, intestinal ultrasound seems important as a first diagnostic tool in young patients without clear symptoms or signs of organic diseases, and can be used as an indication that subsequent invasive tests are required.

[Variant syndromes in autoimmune hepatic diseases]. / Sindromi varianti nelle epatopatie autoimmuni.

Some autoimmune hepatic diseases patterns can be of difficult classification, sometimes as overlap of autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and chronic viral hepatitis. The recognition of these forms is not so easy, but it is necessary for an effective therapeutic approach. At present, the specificity in these cases of the score system done and revised by the International Autoimmune Hepatitis Group is being discussed. Patients showing such diseases have different modalities of presentation of their hepatic disease and different courses. The role of histology appears to be important, but often the overlap of more manifestations is not helpful to a correct diagnostic definition. The variant syndromes could be classified as intermediate patterns of cholestatic forms and of autoimmune hepatic diseases or cholestatic forms of autoimmune hepatitis or hepatitic forms of cholestatic syndromes.

[Abdominal pain and bowel dysfunction: diagnostic flow-chart could be simplified?]. / Dolore addominale e alterazione dell'alvo: è possibile semplificare l'iter diagnostico?

BACKGROUND: The aim of the study was to evaluate the diagnostic role of Kruis score and intestinal ultrasound in young patients with abdominal pain and bowel dysfunction. METHODS: Prospective, double blind, case-control study in 297 consecutive patients with Crohn's disease and irritable bowel syndrome (from 1993 to 1995). INCLUSION CRITERIA: abdominal pain, bowel dysfunction without clear symptoms or signs of organic disease. The final diagnosis is obtained with usual diagnostic criteria and confirmed by at least 2 years of follow-up. Intestinal ultrasound is considered diagnostic of Crohn's disease if bowel wall thickness is = or > 7 mm; the Kruis score is diagnostic for irritable bowel syndrome if = or > 44. RESULTS: To diagnose Crohn's disease, intestinal ultrasound and Kruis score respectively showed sensitivity of 84 and 97%, specificity of 98 and 50%, positive predictive value of 91 and 33%, negative predictive value of 96 and 98%, efficacy of 95 and 60%. Both exams suggest the same diagnosis in 55% of patients with a correct diagnosis of 97%. CONCLUSIONS: The intestinal ultrasound and the Kruis score can be a good diagnostic association in young patients with abdominal pain and bowel dysfunction but without clear symptoms or signs of organic disease. If their diagnostic conclusions are the same (55%), they have a low probability of diagnostic error (3%). If they show a different diagnostic hypothesis, other markers of disease, for example ASCA, can be used.

Detection of anti-Saccharomyces cerevisiae antibodies in Crohn's disease: is it a reliable diagnostic and prognostic marker?

BACKGROUND: In the past few years, serologic markers have been proposed in inflammatory bowel disease. Anti-Saccharomyces cerevisiae antibodies showed high specificity for Crohn's disease. A prognostic role for serology has also been hypothesised. AIMS: To evaluate anti-Saccharomyces cerevisiae antibody distribution in an unselected Italian inflammatory bowel disease population. To analyse whether anti-Saccharomyces cerevisiae antibody status (positive/negative) and/or anti-Saccharomyces cerevisiae antibody titres are associated with clinical variables and outcome measures in Crohn's disease patients. PATIENTS AND METHODS: A series of 299 inflammatory bowel disease patients were evaluated; serum samples were taken and a short clinical history was recorded. anti-Saccharomyces cerevisiae antibodies IgG enzyme-linked immunosorbent assay Medilab (Milan, Italy) kit was used in order to determine anti-Saccharomyces cerevisiae antibody status. RESULTS: Sensitivity, specificity and likelihood ratio for positive test in the differential diagnosis of inflammatory bowel disease was 59%, 89%, 8.1, respectively. Clinical variables significantly associated with anti-Saccharomyces cerevisiae antibody status in logistic regression were found to be ileal location (p=0.01) and earlier age at diagnosis (p<0.01). Among ileal Crohn's disease patients, there was a trend in concordance between anti-Saccharomyces cerevisiae antibody titres and higher number of surgical procedures which was not statistically significant applying more complex statistics. CONCLUSIONS: In an Italian inflammatory bowel disease population, anti-Saccharomyces cerevisiae antibodies status showed characteristics similar to those previously reported. Anti-Saccharomyces cerevisiae antibody positivity is associated with ileal involvement and with earlier onset of Crohn's disease.

[Abdominal pain and bowel dysfunction: the diagnostic role of ultrasonography]. / Dolore addominale e alterazione dell'alvo. Ruolo diagnostico dell'ecotomografia.

PURPOSE: To evaluate the role of intestinal ultrasound (US) in differentiating organic from functional bowel disease. MATERIAL AND METHODS: We examined with abdominal and intestinal US 313 consecutive outpatients presenting abdominal pain and bowel dysfunction, lasting more than 3 months, with no symptoms or signs of alarm and with no previous diagnosis of organic disease. Our population consisted of 191 women and 122 men, with average age at diagnosis of 36.5 years; 236 of these patients had irritable bowel syndrome, 61 Crohn's disease, and 16 ulcerative colitis. Intestinal wall thickness exceeding 7 mm was considered diagnostic for inflammatory bowel diseases. We compared US findings with the diagnosis made with the conventional diagnostic workup of radiological and endoscopic examinations. RESULTS: Sensitivity of intestinal US for diagnosis of inflammatory bowel diseases was 74% and specificity 98% (respectively 84% and 98% for the diagnosis of Crohn's disease and 38% and 98% for ulcerative colitis), and positive and negative predictive values were both 92%; efficacy was also 92%. The likelihood ratio was 35 if US was positive for inflammatory bowel diseases and 0.26 if bowel wall thickness was less than 7 mm. Diagnostic efficacy was 95% for Crohn's disease and 94% for ulcerative colitis. DISCUSSION: Intestinal US proved to be a valuable tool in diagnosing Crohn's disease. As the first step examination US can show the disease site and suggest further instrumental tests. CONCLUSIONS: In our experience intestinal US is an important diagnostic examination for the approach to young patients without symptoms or signs suggestive of organic diseases and can help avoid invasive instrumental examinations.