Showing papers in "Alimentary Pharmacology & Therapeutics in 2014"

Competing risks and prognostic stages of cirrhosis: A 25-year inception cohort study of 494 patients

Abstract: Summary Background Morphological, haemodynamic and clinical stages of cirrhosis have been proposed, although no definite staging system is yet accepted for clinical practice. Aim To investigate whether clinical complications of cirrhosis may define different prognostic disease stages. Methods Analysis of the database from a prospective inception cohort of 494 patients. Decompensation was defined by ascites, bleeding, jaundice or encephalopathy. Explored potential prognostic stages: 1, compensated cirrhosis without oesophago-gastric varices; 2, compensated cirrhosis with varices; 3, bleeding without other complications; 4, first nonbleeding decompensation; 5, any second decompensating event. Patient flow across stages was assessed by a competing risks analysis. Results Major patient characteristics were: 199 females, 295 males, 404 HCV+, 377 compensated, 117 decompensated cirrhosis. The mean follow-up was 145 ± 109 months without dropouts. Major events: 380 deaths, 326 oesophago-gastric varices, 283 ascites, 158 bleeding, 146 encephalopathy, 113 jaundice, 126 hepatocellular carcinoma and 19 liver transplantation. Patients entering each prognostic stage along the disease course were: 202, stage 1; 216, stage 2; 75 stage 3; 206 stage 4; 213 stage 5. Five-year transition rate towards a different stage, for stages 1–4 was 34.5%, 42%, 65% and 78%, respectively (P < 0.0001); 5-year mortality for stages 1–5 was 1.5%, 10%, 20%, 30% and 88% respectively (P < 0.0001). An exploratory analysis showed that this patient stratification may configure a prognostic system independent of the Child–Pugh score, Model for End Stage Liver Disease and comorbidity. Conclusion The development of oesophago-gastric varices and decompensating events in cirrhosis identify five prognostic stages with significantly increasing mortality risks.

Randomised clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis.

Abstract: Background Gut microbiota modifiers may have beneficial effects of non-alcoholic fatty liver disease (NAFLD) but randomised controlled trials (RCT) are lacking in children.

Review article: the epidemiology and prevention of gastric cancer

Abstract: SummaryBackground Gastric cancer can be divided into cardia and noncardia gastric adenocarcinoma (NCGA). Non cardia gastric cancer is a disease that has declined in global incidence but has remained as an extremely lethal cancer. Aim To review recent advances in epidemiology and strategies in prevention of non cardia gastric cancer. Methods A rapid literature search strategy was developed for all English language literature published before March 2013. The search was conducted using the electronic databases PubMed and EMBASE. The search strategy included the keywords ‘stomach neoplasms’, ‘gastric cancer’, ‘epidemiology’, ‘risk factor’, ‘early detection of cancer’, ‘mass screening’, ‘cancer burden’, ‘prevention’ and ‘cost-effectiveness’. The search strategy was adjusted according to different requirements for each database. The specific search was also performed in cancer-related websites for country-specific information. The search was limited to past 10 years. Results Gastric cancer is the fifth most common cancer but the third leading cause of cancer death. The case fatality rate is 75%. Screening by radiological or endoscopic methods has limited success in prevention of gastric cancer. Helicobacter pylori has been identified as a carcinogen, accounting for 60–70% of gastric cancer globally and eradication is a potential preventive measure. A meta-analysis in 2009 demonstrated that individuals treated with H. pylori eradication therapy can reduce gastric cancer risk. The extended Shandong Intervention trial that lasted 14.3 years showed that H. pylori eradication therapy significantly reduced gastric cancer incidence by 39%. Consensus groups from Asia, Europe and Japan have recommended H. pylori eradication as primary prevention in high-risk areas. Following eradication therapy, endoscopic surveillance of pre-malignant lesions using enhanced imaging appears to be another promising preventive strategy. Conclusions Gastric cancer remains a major diagnostic and therapeutic challenge. There is emerging evidence that H. pylori eradication in high gastric cancer regions can lead to a decline in the incidence of this highly lethal disease.

Review article: the economic impact of the irritable bowel syndrome.

Abstract: Background: Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal system affecting a large number of people worldwide. Whilst it has no attributable mortality, it has substantial impact on patients' quality of life (QoL) and is associated with considerable healthcare resource use. Aim: To review the economic impact of IBS, firstly on the individual, secondly on healthcare systems internationally and thirdly to society. Methods: Appropriate databases were searched for relevant papers using the terms: Irritable Bowel Syndrome; IBS; irritable colon; functional bowel/colonic disease; economics; health care/service costs; health expenditure/resources; health care/service utilisation; productivity. Results: Irritable bowel syndrome impacts most substantially on patients' work and social life. Reduction in QoL is such that on average patients would sacrifice between 10 and 15 years of their remaining life expectancy for an immediate cure. Between 15% and 43% of patients pay for remedies. No studies quantify loss of earnings related to IBS. Direct care costs are substantial; 48% of patients incur some costs in any year with annual international estimates per patient of: USA $742–$7547, UK £90–£316, France €567–€862, Canada $259, Germany €791, Norway NOK 2098 (€262) and Iran $92. Minimising extensive diagnostic investigations could generate savings and has been shown as not detrimental to patients. Cost to industry internationally through absenteeism and presenteeism related to IBS is estimated between £400 and £900 per patient annually. Conclusions: costs to patients, healthcare systems and society. Considerable benefit could be obtained from effective interventions.

Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease--the role of transient elastography and plasma cytokeratin-18 fragments.

Abstract: SummaryBackground Non-alcoholic fatty liver disease (NAFLD) affects 15–40% of the general population. Some patients have non-alcoholic steatohepatitis (NASH) and progressive fibrosis, and would be candidates for monitoring and treatment. Aim To review current literature on the use of non-invasive tests to assess the severity of NAFLD. Methods Systematic literature searching identified studies evaluating non-invasive tests of NASH and fibrosis using liver biopsy as the reference standard. Meta-analysis was performed for areas with adequate number of publications. Results Serum tests and physical measurements like transient elastography (TE) have high negative predictive value (NPV) in excluding advanced fibrosis in NAFLD patients. The NAFLD fibrosis score comprises of six routine clinical parameters and has been endorsed by current American guidelines as a screening test to exclude low-risk individuals. The pooled sensitivities and specificities for TE to diagnose F ≥ 2, F ≥ 3 and F4 disease were 79% and 75%, 85% and 85%, and 92% and 92% respectively. Liver stiffness measurement often fails in obese patients, but the success rate can be improved with the use of the XL probe. A number of biomarkers have been developed for the diagnosis of NASH, but few were independently validated. Serum/plasma cytokeratin-18 fragments have been most extensively evaluated and have a pooled sensitivity of 66% and specificity of 82% in diagnosing NASH. Conclusions Current non-invasive tests are accurate in excluding advanced fibrosis in NAFLD patients, and may be used for initial assessment. Further development and evaluation of NASH biomarkers are needed.

Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease

Abstract: SummaryBackground Several steatosis biomarkers are available with limited independent validation. Aim To determine diagnostic value and limitations of several steatosis biomarkers using liver biopsy as reference standard in a large cohort of patients with suspected NAFLD. Methods Three hundred and twenty-four consecutive liver biopsies were included. Histological steatosis was categorised as none ( 66%). Five steatosis biomarkers were measured: fatty liver index (FLI), NAFLD liver fat score (NAFLD-LFS), hepatic steatosis index (HSI), visceral adiposity index (VAI) and triglyceride × glucose (TyG) index. Results Steatosis grades prevalence was: none 5%, mild 39%, moderate 30% and severe 27%. Except for VAI, the steatosis biomarkers showed a linear trend across the steatosis grades. However, their correlation with the histological amount of steatosis was only weak-moderate. All steatosis biomarkers had an adequate diagnostic accuracy for the presence of steatosis: AUROCs for FLI, LFS, HSI, VAI and TyG were 0.83, 0.80, 0.81, 0.92 and 0.90. However, their ability to quantify steatosis was poor: none of them distinguished between moderate and severe steatosis and the AUROCs for predicting steatosis >33% were 0.65, 0.72, 0.65, 0.59 and 0.59 for FLI, LFS, HSI, VAI and TyG. Both fibrosis and inflammation significantly confounded the association between steatosis biomarkers and steatosis. The steatosis biomarkers were all correlated with HOMA-IR, independent from histological steatosis. Conclusions All five steatosis biomarkers can diagnose steatosis and are correlated with insulin resistance. They are confounded by fibrosis and inflammation, and do not accurately quantify steatosis; this may limit their clinical utility. More research is needed to identify truly independent and quantitative markers of steatosis.

Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications.

Abstract: SummaryBackground Gastrointestinal mucositis is defined as inflammation and/or ulcers of the gastrointestinal tract occurring as a complication of chemotherapy and radiation therapy, and affects about 50% of all cancer patients. Aim To assess the role of gut microbiota in the pathogenesis of gastrointestinal mucositis and the potential for manipulations of the microbiota to prevent and to treat mucositis. Methods Search of the literature published in English using Medline, Scopus and the Cochrane Library, with main search terms ‘intestinal microbiota’, ‘bacteremia’, ‘mucositis’, ‘chemotherapy-induced diarrhoea’, ‘chemotherapy-induced mucositis’, ‘radiotherapy-induced mucositis’. Results The gut microbiota plays a major role in the maintenance of intestinal homoeostasis and integrity. Patients receiving cytotoxic and radiation therapy exhibit marked changes in intestinal microbiota, with most frequently, decrease in Bifidobacterium, Clostridium cluster XIVa, Faecalibacterium prausnitzii, and increase in Enterobacteriaceae and Bacteroides. These modifications may contribute to the development of mucositis, particularly diarrhoea and bacteraemia. The prevention of cancer therapy-induced mucositis by probiotics has been investigated in randomised clinical trials with some promising results. Three of six trials reported a significantly decreased incidence of diarrhoea. One trial reported a decrease in infectious complications. Conclusions The gut microbiota may play a major role in the pathogenesis of mucositis through the modification of intestinal barrier function, innate immunity and intestinal repair mechanisms. Better knowledge of these effects may lead to new therapeutic approaches and to the identification of predictive markers of mucositis.

Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.

Abstract: SummaryBackground Safety of individual probiotic strains approved under Investigational New Drug (IND) policies in cirrhosis with minimal hepatic encephalopathy (MHE) is not clear. Aim The primary aim of this phase I study was to evaluate the safety, tolerability of probiotic Lactobacillus GG (LGG) compared to placebo, while secondary ones were to explore its mechanism of action using cognitive, microbiome, metabolome and endotoxin analysis in MHE patients. Methods Cirrhotic patients with MHE patients were randomised 1:1 into LGG or placebo BID after being prescribed a standard diet and multi-vitamin regimen and were followed up for 8 weeks. Serum, urine and stool samples were collected at baseline and study end. Safety was assessed at Weeks 4 and 8. Endotoxin and systemic inflammation, microbiome using multi-tagged pyrosequencing, serum/urine metabolome were analysed between groups using correlation networks. Results Thirty MHE patients (14 LGG and 16 placebo) completed the study without any differences in serious adverse events. However, self-limited diarrhoea was more frequent in LGG patients. A standard diet was maintained and LGG batches were comparable throughout. Only in the LGG-randomised group, endotoxemia and TNF-α decreased, microbiome changed (reduced Enterobacteriaceae and increased Clostridiales Incertae Sedis XIV and Lachnospiraceae relative abundance) with changes in metabolite/microbiome correlations pertaining to amino acid, vitamin and secondary BA metabolism. No change in cognition was found. Conclusions In this phase I study, Lactobacillus GG is safe and well-tolerated in cirrhosis and is associated with a reduction in endotoxemia and dysbiosis.

Review article: the nutritional and pharmacological consequences of obesity surgery

Abstract: SummaryBackground Obesity surgery is acknowledged as a highly effective therapy for morbidly obese patients. Beneficial short-term effects on common comorbidities are practically undisputed, but a growing data pool from long-term follow-up reveals increasing evidence of potentially severe nutritional and pharmacological consequences. Aims To assess the prevalence, causes and symptoms of complications after obesity surgery, to elucidate and compare therapy recommendations for macro- and micronutrient deficiencies, and to explore surgically-induced effects on drug absorption and bioavailability, discussing ramifications for long-term therapy and prophylaxis. Methods PubMed, Embase and MEDLINE were searched using terms including, but not limited to, bariatric surgery, gastric bypass, obesity surgery and Roux-en-Y, coupled with secondary search terms, e.g. anaemia, micronutrients, vitamin deficiency, bacterial overgrowth, drug absorption, pharmacokinetics, undernutrition. All studies in English, French or German published January 1980 through March 2014 were included. Results Macro- and micronutrient deficiencies are common after obesity surgery. The most critical, depending on surgical technique, are hypoalbuminemia (3–18%) and deficiencies of vitamins B1 (≤49%), B12 (19–35%) and D (25–73%), iron (17–45%) and zinc (12–91%). Many drugs commonly administered to obese patients (e.g. anti-depressants, anti-microbials, metformin) are subject to post-operative and/or PPI-associated changes affecting bioavailability and absorption. Conclusions Complications are associated with pre-operative and/or post-operative malnutrition or procedure-related changes in intake, absorption and drug bioavailability. The high prevalence of nutrient deficiencies after obesity surgery makes life-long nutritional monitoring and supplementation essential. Post-operative changes to drug absorption and bioavailability in bariatric patients cast doubt on the validity of standard drug dosage and administration recommendations.

Systematic review with meta-analysis: the declining risk of colorectal cancer in ulcerative colitis.

Abstract: Summary Background Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer (CRC); however, the magnitude of this effect is open to debate. Aim To assess the risk of CRC in UC patients by systematic review and meta-analysis. Methods A systematic literature search was performed up to November 2013. We selected studies describing the incidence and prevalence of CRC in patients with UC. Articles were assessed for quality using the Newcastle-Ottawa Scale. Cumulative incidence and incidence rates of CRC were combined and analysed using the generic inverse variance method. Sub-analyses were performed to identify factors associated with an increased risk of developing CRC. Results A total of 81 studies (181 923 patients) met the inclusion criteria. The incidence rate of CRC in patients with UC was 1.58 per 1000 patient-years (py) [95% confidence interval (CI), 1.39–1.76]. Results were heterogeneous (I2 = 81–89%). The incidence rate was 4.02/1000 py (95%CI = 2.74–5.31) in studies that only included patients with extensive colitis, and 1.24/1000 py (95%CI = 1.01–1.47) in population-based studies. The incidence rate was 0.91/1000 py (95%CI = 0.61–1.2) in the first decade of disease, 4.07/1000 py (95%CI = 2.58–5.56) in the second, and 4.55/1000 py (95%CI = 2.64–6.46) in the third. The incidence rate decreased from 4.29/1000 py in the studies published in the 1950s to 1.21/1000 py in studies published in the last decade. Conclusions The risk of patients with ulcerative colitis developing colorectal cancer has decreased steadily over the last six decades, but the extent and duration of the disease increase this risk.

Review article: gastrointestinal angiodysplasia - pathogenesis, diagnosis and management.

Abstract: SummaryBackground Angiodysplasia (AD) of the gastrointestinal (GI) tract is an important condition that can cause significant morbidity and –rarely – mortality. Aim To provide an up-to-date comprehensive summary of the literature evaluating this disease entity with a particular focus on pathogenesis as well as current and emerging diagnostic and therapeutic modalities. Recommendations for treatment will be made on the basis of the current available evidence and consensus opinion of the authors. Methods A systematic literature search was performed. The search strategy used the keywords ‘angiodysplasia’ or ‘arteriovenous malformation’ or ‘angioectasia’ or ‘vascular ectasia’ or ‘vascular lesions’ or ‘vascular abnormalities’ or ‘vascular malformations’ in the title or abstract. Results Most AD lesions (54–81.9%) are detected in the caecum and ascending colon. They may develop secondary to chronic low-grade intermittent obstruction of submucosal veins coupled with increased vascular endothelial growth factor-dependent proliferation. Endotherapy with argon plasma coagulation resolves bleeding in 85% of patients with colonic AD. In patients who fail (or are not suitable for) other interventions, treatment with thalidomide or octreotide can lead to a clinically meaningful response in 71.4% and 77% of patients respectively. Conclusions Angiodysplasia is a rare, but important, cause of both overt and occult GI bleeding especially in the older patients. Advances in endoscopic imaging and therapeutic techniques have led to improved outcomes in these patients. The choice of treatment should be decided on a patient-by-patient basis. Further research is required to better understand the pathogenesis and identify potential therapeutic targets.

Review article: vitamin D and inflammatory bowel diseases

Abstract: SummaryBackground Vitamin D is traditionally associated with bone metabolism. The immunological effects of vitamin D have increasingly come into focus. Aim To review the evidence supporting a role of vitamin D in inflammatory bowel diseases. Methods A comprehensive search was performed on PubMed using the terms ‘crohn's disease’ ‘ulcerative colitis’ and ‘vitamin D’. Results Vitamin D deficiency is common in patients with inflammatory bowel diseases (IBD) (16–95%) including those with recently diagnosed disease. Evidence supports immunological role of vitamin D in IBD. In animal models, deficiency of vitamin D increases susceptibility to dextran sodium sulphate colitis, while 1,25(OH)2D3 ameliorates such colitis. One prospective cohort study found low predicted vitamin D levels to be associated with an increased risk of Crohn's disease (CD). Limited data also suggest an association between low vitamin D levels and increased disease activity, particularly in CD. In a large cohort, vitamin D deficiency (<20 ng/mL) was associated with increased risk of surgery (OR 1.8, 95% CI 1.2–2.5) in CD and hospitalisations in both CD (OR 2.1, 95% CI 1.6–2.7) and UC (OR 2.3, 95% CI 1.7–3.1). A single randomised controlled trial demonstrated that vitamin D supplementation may be associated with reduced frequency of relapses in patients with CD compared with placebo (13% vs. 29%, P = 0.06). Conclusions There is growing epidemiological evidence to suggest a role for vitamin D deficiency in the development of IBD and also its influence on disease severity. The possible therapeutic role of vitamin D in patients with IBD merits continued investigation.

Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn's disease

Abstract: SummaryBackground Adalimumab is an effective treatment for Crohn's disease (CD). Anti-adalimumab antibodies (AAA) and low trough serum drug concentrations have been implicated as pre-disposing factors for treatment failure. Aims To assess adalimumab and AAA serum levels, and to examine their association and discriminatory ability with clinical response and serum C-reactive protein (CRP). Methods We performed a cross-sectional study using trough sera from adalimumab-treated CD patients. Demographical data, Montreal classification, treatment regimen and clinical status were recorded. Serum adalimumab, AAA and CRP were measured. Receiver operating characteristic analysis and a multivariate regression model were performed to find drug and antibody thresholds for predicting disease activity at time of serum sampling. Results One hundred and eighteen trough serum samples were included from 71 patients. High adalimumab trough serum concentration was associated with disease remission (Area Under Curve 0.748, P < 0.001). A cut-off drug level of 5.85 μg/mL yielded optimal sensitivity, specificity and positive likelihood ratio for remission prediction (68%, 70.6% and 2.3, respectively). AAA were inversely related with adalimumab drug levels (Spearman's r = −0.411, P < 0.001) and when subdivided into categorical values, positively related with disease activity (P < 0.001). High drug levels and stricturing vs. penetrating or inflammatory phenotype, but not AAA levels, independently predicted disease remission in a multivariate logistic regression model. Conclusions Adalimumab drug levels were inversely related to disease activity. High levels of anti-adalimumab antibodies were positively associated with disease activity, but this association was mediated mostly by adalimumab drug levels.

Systematic review with meta‐analysis: the effects of rifaximin in hepatic encephalopathy

Abstract: SummaryBackground Rifaximin is recommended for prevention of hepatic encephalopathy (HE). The effects of rifaximin on overt and minimal HE are debated. Aim To perform a systematic review and meta-analysis of randomised controlled trials (RCTs) on rifaximin for HE. Methods We performed electronic and manual searches, gathered information from the U.S. Food and Drug Administration Home Page, and obtained unpublished information on trial design and outcome measures from authors and pharmaceutical companies. Meta-analyses were performed and results presented as risk ratios (RR) with 95% confidence intervals (CI) and the number needed to treat. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate the risk of bias and sources of heterogeneity. Results We included 19 RCTs with 1370 patients. Outcomes were recalculated based on unpublished information of 11 trials. Overall, rifaximin had a beneficial effect on secondary prevention of HE (RR: 1.32; 95% CI 1.06–1.65), but not in a sensitivity analysis on rifaximin after TIPSS (RR: 1.27; 95% CI 1.00–1.53). Rifaximin increased the proportion of patients who recovered from HE (RR: 0.59; 95% CI: 0.46–0.76) and reduced mortality (RR: 0.68, 95% CI 0.48–0.97). The results were robust to adjustments for bias control. No small study effects were identified. The sequential analyses only confirmed the results of the analysis on HE recovery. Conclusions Rifaximin has a beneficial effect on hepatic encephalopathy and may reduce mortality. The combined evidence suggests that rifaximin may be considered in the evidence-based management of hepatic encephalopathy.

Systematic review with network meta‐analysis: the efficacy of anti‐TNF agents for the treatment of Crohn's disease

Abstract: SummaryBackground Anti-tumour necrosis factor-alpha agents (anti-TNF) are effective therapies for the treatment of Crohn's disease (CD), but their comparative efficacy is unknown. Aim To perform a network meta-analysis comparing the efficacy of anti-TNF therapies in CD. Methods After screening 506 studies, reviewers extracted information on 10 studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. Results Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 1.66, 95% CI: 1.17–2.36 and RR: 1.43, 95% CI: 1.17–1.73, respectively) as well as maintenance of remission and response (RR: 1.78, 95% CI: 1.51–2.09 and RR: 1.68, 95% CI: 1.46–1.93, respectively). NMA found nonsignificant trends between infliximab and adalimumab or certolizumab pegol. Among subcutaneous therapies, NMA demonstrated superiority of adalimumab to certolizumab pegol for induction of remission (RR: 2.93, 95% CrI: 1.21–7.75). Sample size calculations suggest that adequately powered head-to-head comparative efficacy trials would require greater than 3000 patients. Conclusions All anti-TNF agents are effective for induction and maintenance of response and remission in the treatment of CD. Although adalimumab is superior to certolizumab pegol for induction of remission, there is no evidence of clinical superiority among anti-TNF agents. Head-to-head trials among the anti-TNF agents are impractical in terms of size and cost.

Olmesartan-associated enteropathy: results of a national survey

Abstract: BACKGROUND: Recently, a new enteropathy has been described: olmesartan-associated enteropathy. However, the association has been questioned: a phase 3 trial and a cohort study found no association between gastrointestinal events and olmesartan. AIM: To collect French cases of sartan-associated enteropathy to describe further this entity, confirm or refute causality, and determine if the association exists with other sartans. METHODS: French gastroenterologists were invited to report cases of sartan-associated enteropathy and collect clinical, biological and histological data. Patients with diarrhoea and histological duodenal abnormalities were included. RESULTS: Thirty-six patients with olmesartan-associated enteropathy were reported, including 32 with villous atrophy and four without. There was only one patient with irbesartan-associated enteropathy. None of the patients died. Patients with villous atrophy had diarrhoea, vomiting, renal failure, hypokalaemia, body weight loss and hypoalbuminaemia. Thirty-one patients were hospitalised; four required intensive care. Anti-transglutaminase and anti-enterocyte antibodies were negative; anti-nuclear antibodies were positive (9/11). Endoscopic duodenal biopsies showed villous atrophy (32/32) and polyclonal intra-epithelial CD3+CD8+ lymphocytosis (11/11). Exactly, 14/15 patients responded to steroids and/or immunosuppressants, prescribed because of suspected autoimmune enteropathy. Ten olmesartan interruptions were followed by reintroductions before steroids or immunosuppressants. Interruptions were followed by remissions (9/10), but reintroductions were followed by relapses (9/9). Twenty-nine patients were in remission since olmesartan interruption, including 26 without immunosuppressants. Patients with normal villi had similar clinical characteristics, but mild histological abnormalities (intra-epithelial lymphocytosis and lamina propria lymphocytic infiltration). CONCLUSIONS: Olmesartan causes a severe and immune-mediated enteropathy, with or without villous atrophy. Enteropathy associated with other sartans seems to be very rare.

Systematic review with meta-analysis : associations between coeliac disease and type 1 diabetes

Abstract: SummaryBackground In the past decade, a number of population-based studies have examined the prevalence of coeliac disease in individuals with type 1 diabetes but prevalences have differed considerably. Aim To examine the prevalence of coeliac disease in individuals with type 1 diabetes. Methods A systematic review of English-language articles published in PubMed Medline between 2000 and May 2014. Search terms included ‘celiac disease’ or ‘coeliac disease’ and ‘diabetes mellitus’. Studies were selected with at least 100 individuals with type 1 diabetes being screened for coeliac disease where the coeliac diagnosis was later confirmed through small intestinal biopsy. Data synthesis used random-effects inverse variance-weighted models, and metaregression was used to examine heterogeneity in subgroups. Results A pooled analysis, based on 26,605 patients with type 1 diabetes, found a prevalence of biopsy-confirmed coeliac disease of 6.0% (95% CI = 5.0–6.9%). Heterogeneity was large (I2 = 93.2%). The prevalence was lower in adults with type 1 diabetes (2.7%), and in mixed populations with both children and adults with type 1 diabetes (4.7%) than in children (6.2%) with type 1 diabetes (P < 0.001). Additional subgroup analyses could not explain the large variation in coeliac disease prevalence between studies. Conclusion More than one in twenty patients with type 1 diabetes have biopsy-verified coeliac disease. This prevalence is high enough to motivate screening for coeliac disease among patients with type 1 diabetes.

Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets.

Abstract: SummaryBackground Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disease with a substantial social and economic burden. Treatment options remain limited and research on the aetiology and pathophysiology of this multifactorial disease is ongoing. Aim To discuss the potential role of gut microbiota in the pathophysiology of IBS and to identify possible interactions with pathophysiologic targets in IBS. Methods Articles were identified via a PubMed database search [‘irritable bowel syndrome’ AND (anti-bacterial OR antibiotic OR flora OR microbiota OR microflora OR probiotic)]. English-language articles were screened for relevance. Full review of publications for the relevant studies was conducted, including additional publications that were identified from individual article reference lists. Results The role of gut microbiota in IBS is supported by varying lines of evidence from animal and human studies. For example, post-infectious IBS in humans is well documented. In addition, certain probiotics and nonsystemic antibiotics appear to be efficacious in the treatment of IBS. Mechanisms involved in improving IBS symptoms likely go beyond mere changes in the composition of the gut microbiota, and accumulating animal data support the interplay of microbiota with other IBS targets, such as the gut–brain axis, visceral hypersensitivity, mucosal inflammation and motility. Conclusion The role of the gut microbiota is still being elucidated; however, it appears to be one of several important factors that contributes to the aetiology and pathophysiology of the irritable bowel syndrome.

Review article: anti-adhesion therapies for inflammatory bowel disease.

Abstract: SummaryBackground A high proportion of patients with inflammatory bowel disease (IBD) do not achieve clinical remission with the current therapies including mesalazine (mesalamine), immunossupresants (IMS) and antibodies against tumour necrosis factor (anti-TNF). Moreover, IMS and anti-TNF involve a nonnegligible risk for infections and/or malignancies. The anti-adhesion molecules are one of the most interesting new treatments because of their gut-selectivity. Aim To review the physiopathology of the adhesion molecules and the current drugs targeting this mechanism. Methods We performed a literature review in PubMed and in clinicaltrials.gov using the terms ‘anti-adhesion molecules’, ‘inflammatory bowel disease’, ‘natalizumab’, ‘vedolizumab’, ‘AMG181’, ‘Etrolizumab’, ‘PF-00547659’, ‘AJM300’, ‘Alicaforsen’ and ‘CCX282-B’ up to November 2013. Results A total of eight drugs were found including those targeting the α4β1, α4β7 or αEβ7 integrins as well as the ICAM-1 and MAdCAM-1 addressins and the chemokine receptor 9. The rationale for these drugs is the blockade of gut-homing T lymphocytes and the ones targeting the α4β7/MAdCAM-1 interaction presented the most promising results in luminal disease. Vedolizumab, an α4β7 antibody, has completed phase 3 trials with very positive results especially for ulcerative colitis. However, many questions remain unanswered such as the effect of these therapies in perianal disease and extraintestinal manifestations. Conclusions The blockade of the α4β7/MAdCAM-1 interaction and especially vedolizumab is an effective and safe gut-specific treatment for IBD. Further studies are needed to clarify the efficacy and safety of the other anti-adhesion drugs and to define the specific indications of these therapies in the different scenarios of IBD.

Review article: the investigation and management of rectal neuroendocrine tumours.

Abstract: SummaryBackground Gastric carcinoids (GCs) or neuroendocrine tumours (NETs) are increasingly identified at endoscopy, and account for 0.6–2% of all gastric polyps identified. The SEER database in the US has demonstrated a rising incidence of gastric NETs amongst all NETs; from 2.2% between 1950 and 1969 to 6.0% between 2000 and 2007. Aim To review the literature and assist clinicians in managing patients with GCs. Methods A literature search was conducted through MEDLINE using search terms: gastric, carcinoid, neuroendocrine tumour, therapy, endoscopy, mucosal resection, submucosal dissection. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles. Results There are three types of GCs with important epidemiological, pathophysiological, histological and endoscopic differences that affect prognosis and management. Type 1 and 2 GCs develop in the context of hypergastrinaemia that originates from achlorhydria in atrophic gastritis and a gastrinoma, respectively. Type 3 GCs occur sporadically and independent of gastrin. The histological type, grade and Ki67 index are used to determine prognosis and direct clinical management. Type 1 GCs >1 cm in size and type 2 GCs should be assessed for invasion beyond the submucosa with EUS prior to endoscopic resection with EMR or ESD. Type 3 GCs should be managed as per recommendations for gastric adenocarcinoma. The treatment of advanced disease is multimodal. Conclusions Patients with gastric carcinoids should be discussed in a specialist neuroendocrine tumour multidisciplinary meeting to ensure all treatment options are explored in localised and advanced disease. Areas of controversy exist that need further research.

Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis.

Abstract: SummaryBackground Antibodies against tumour necrosis factor-alpha (anti-TNF) are effective therapies in the treatment of ulcerative colitis (UC), but their comparative efficacy is unknown. Aim To perform a network meta-analysis comparing the efficacy of anti-TNF agents in UC. Methods After screening 506 studies, reviewers extracted information on seven studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. Results Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 2.45, 95% CI: 1.72–3.47 and RR: 1.65, 95% CI: 1.37–1.99 respectively) as well as maintenance of remission and response (RR: 2.00, 95% CI: 1.52–2.62 and RR: 1.76, 95% CI: 1.46–2.14 respectively). Individually, infliximab, adalimumab and goliumumab resulted in a higher likelihood of induction and maintenance for both remission and response. NMA found nonsignificant trends in comparisons of the individual agents. The required sample sizes for direct head-to-head trials between infliximab and adalimumab for induction and maintenance are 174 and 204 subjects respectively. Conclusions This study demonstrates that, compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis. However, network meta-analysis demonstrates that no single agent is clinically superior to the others and therefore, other factors such as cost, safety, route of administration and patient preference should dictate our choice of anti-TNF agents. A randomised comparative efficacy trial between infliximab and adalimumab in UC is of practical size and should be performed.

Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor-α therapy in inflammatory bowel disease.

Abstract: Summary Background Anti-tumour necrosis factor-α (TNFα) antibodies are efficacious in inflammatory bowel disease (IBD). These drugs carry the theoretical risk of malignancy, particularly lymphoma, but no systematic review and meta-analysis has examined this issue. Aim To pool data from all available placebo-controlled studies to estimate risk of malignancy with anti-TNFα therapy in IBD. Methods MEDLINE, EMBASE and the Cochrane central register of controlled trials were searched to November 2013. Randomised controlled trials (RCTs) comparing anti-TNFα therapy with placebo in adults with Crohn's disease (CD) or ulcerative colitis (UC) were eligible. Data were pooled to obtain a relative risk (RR) of malignancy with a 95% confidence interval (CI). Results The search strategy identified 25 338 citations, of which 22 RCTs were eligible (11 infliximab, six adalimumab, four certolizumab and one golimumab) involving 7054 patients (4566 CD and 2488 UC). In total, there were 16 (0.39%) malignancies in 4135 IBD patients allocated to anti-TNFα, compared with 13 (0.45%) in 2919 patients randomised to placebo. There were no cases of lymphoma in the active treatment group, compared with three (0.1%) in the control group. The RR of malignancy for patients receiving anti-TNFα therapy compared with placebo was 0.77 (95% CI 0.37–1.59). When seven individuals with nonmelanoma skin cancer were excluded from the analysis, the RR was 0.90 (95% CI 0.40–2.02). Conclusions Anti-TNFα therapy was not associated with an increased risk of malignancy in patients with IBD. However, no trials provided data for risk of malignancy beyond 1 year of treatment, meaning that an increased risk in the longer term cannot be excluded.

Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation.

Abstract: Summary Background Highly selective 5-HT4 agonists have been suggested for the treatment of chronic constipation (CC). Aim To assess the effects of highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) on patient-important clinical efficacy outcomes and safety in adults with CC. Methods We searched the medical literature in January 2013 using MEDLINE/Pubmed, Embase, Cochrane Library, and Web of Science/Scopus for randomised, controlled trials of highly selective 5-HT4 agonists in adults with CC, with no minimum duration of therapy (maximum 12 weeks) or date limitations. Data were extracted from intention-to-treat analyses, pooled using a random-effects model, and reported as relative risk (RR), mean differences, or standardised mean differences with 95% confidence intervals (CI). Results Main outcomes included stool frequency, Patient-Assessment of Constipation Quality of Life (PAC-QOL), PAC of symptoms (PAC-SYM) and adverse events. Thirteen eligible trials were identified: 11 prucalopride, 1 velusetrag, 1 naronapride. Relative to control, treatment with highly selective 5-HT4 agonists was superior for all outcomes: mean ≥3 spontaneous complete bowel movements (SCBM)/week (RR = 1.85; 95% CI 1.23–2.79); mean ≥1 SCBM over baseline (RR = 1.57; 95% CI 1.19, 2.06); ≥1 point improvement in PAC-QOL and PAC-SYM scores. The only active comparator trial of prucalopride and PEG3350 suggested PEG3350 is more efficacious for some end points. Adverse events were more common with highly selective 5-HT4 agonists, but were generally minor; headache was the most frequent. Most trials studied prucalopride. Conclusion Demonstration of efficacy on patient-important outcomes and a favourable safety profile support the continued use and development of highly selective 5–HT4 agonists in the treatment of chronic constipation.

Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children

Abstract: Summary Background There has been growing interest in the use of faecal microbiota transplantation (FMT) for the treatment of gastrointestinal and nongastrointestinal diseases. Aim To review systematically the reported efficacy and safety of FMT in the management of gastrointestinal and nongastrointestinal disorders in adults and children. Methods The systematic review followed Cochrane and PRISMA recommendations. Available articles were identified using three electronic databases in addition to hand searching and contacting experts. Inclusion criteria were any reports of FMT therapy written in English. Results A total of 844 patients who had undergone FMT were identified from 67 published studies. The most common indications were refractory/relapsing Clostridium difficile infection (CDI) (76.3%) and inflammatory bowel disease (IBD) (13.2%). There has been only one placebo-controlled trial, a successful trial in 43 patients with recurrent CDI. Seven publications report FMT in paediatric patients with a total of 11 treated, 3 with chronic constipation and the remainder with recurrent CDI or ulcerative colitis (UC). 90.7% of patients with refractory/relapsing CDI were cured and 78.4% of patients with IBD were in remission after FMT. FMT therapy could also be effective in treatment of some nongastrointestinal disorders such as chronic fatigue syndrome. The only reported serious adverse event attributed to the therapy was a case of suspected peritonitis. Conclusions Although more controlled trials are needed, faecal microbiota transplantation therapy shows promise in both adults and children with gastrointestinal diseases such as CDI and IBD.

Systematic review with meta‐analysis: inflammatory bowel disease in the elderly

Abstract: Summary Background Elderly patients represent an increasing proportion of the inflammatory bowel disease (IBD) population. Aim To critically review available data regarding the care of elderly IBD patients. Methods Bibliographic searches (MEDLINE) up to June 2013. Results Approximately 10–15% of cases of IBD are diagnosed in patients aged >60 years, and 10–30% of the IBD population are aged >60 years. In the elderly, IBD is easily confused with other more common diseases, mainly diverticular disease and ischaemic colitis. The clinical features of IBD in older patients are generally similar to those in younger patients. Crohn's disease (CD) in elderly patients is characterised by its predominantly colonic localisation and uncomplicated course. Proctitis and left-sided ulcerative colitis are more common in patients aged >60 years. Infections are associated with age and account for significant mortality in IBD patients. The treatment of IBD in the elderly is generally similar. However, the therapeutic approach in the elderly should be ‘start low-go slow’. The benefit of thiopurines in older CD patients remains debatable. Although the indications for anti-tumour necrosis factors in the elderly are generally similar to those for younger patients, lower response and higher adverse events have been reported in the elderly. Surgery in elderly patients does not generally differ. Ileal pouch-anal anastomosis can be successful, provided the patient retains good anal sphincter function. Conclusions Management of the older IBD patient differs from that of younger patients; therefore, conventional practice algorithms may have to be modified to account for advanced age.

Review article: Herbal hepatotoxicity--an update on traditional Chinese medicine preparations.

Abstract: BACKGROUND: Although evidence for their therapeutic efficacy is limited, herbal traditional Chinese medicine (TCM) preparations increasingly gain popularity. In contrast to other herbal products, adverse effects by herbal TCM including liver toxicity were rarely reported. In recent years, more cases were published, providing new clinical challenges. AIM: To summarise comprehensively the literature on herbal TCM hepatotoxicity since 2011. METHODS: PubMed was searched using key words related to TCM, the results were restricted to full English-language publications and abstracts published since 2011. In addition, the database of the National Institutes of Health (NIH) and LiverTox was accessed under the topic 'Drug record: Chinese and other Asian herbal medicines'. RESULTS: Since 2011, new case reports and case series provided evidence for herbal hepatotoxicity by TCM, focusing on nine TCM herbal mixtures and four individual TCM herbs with potential health hazards. These were the TCM products Ban Tu Wan, Chai Hu, Du Huo, Huang Qin, Jia Wei Xia Yao San, Jiguja, Kamishoyosan, Long Dan Xie Gan Tang, Lu Cha, Polygonum multiflorum products, Shan Chi, 'White flood' containing the herbal TCM Wu Zhu Yu and Qian Ceng Ta, and Xiao Chai Hu Tang. Other developments include the establishment of a new and early diagnostic serum marker for hepatotoxicity caused by pyrrolizidine alkaloids, assessed using ultra performance liquid chromatography-mass spectrometry analysis, and new regulatory details to improve herbal TCM product quality and safety. CONCLUSION: Stringent evaluation of the risk/benefit ratio is essential to protect traditional Chinese medicines users from health hazards including liver injury. Language: en

Nationwide prevalence of inflammatory bowel disease in Sweden: a population‐based register study

Abstract: Summary Background Regional studies on inflammatory bowel disease (IBD) suggest an increasing prevalence over time, but no nationwide estimate has been published so far. Aim To estimate the IBD prevalence in 2010 in Sweden overall, by disease, and in specific patient segments. Methods Patients were identified according to international classification codes for ulcerative colitis and Crohn's disease in in-patient care (1987–2010), day surgery and nonprimary out-patient care (1997–2010) in the nationwide Swedish Patient Register. Results Requiring two or more diagnoses of IBD in nonprimary care, a total of 61 344 individuals with physician-diagnosed IBD were alive in Sweden in 2010 (mean age 50 years; 51% men), corresponding to a prevalence of 0.65% (95% CI, 0.65–0.66). The prevalence increased with age, and peaked in women at ages 50–59 years and in men at ages 60–69 years. Adding the requirement of IBD as main (vs. main or contributory) diagnosis code, or diagnosis from an internal medicine/gastroenterology/surgery department did not change the prevalence estimate. Prevalence of actively treated disease (defined as two or more IBD-related visits, of which one occurred in 2010, plus at least one dispensed prescription of IBD-related drugs in 2010) was 0.27% (95% CI, 0.27–0.28). Conclusions The Swedish nationwide register-based IBD prevalence was higher compared with previous Swedish and international estimates. While prevalence estimates were robust across different case definitions, once two or more visits were required, only about one-third of prevalent patients were drawing resources from specialised care in 2010.

The incidence and risk factors for developing depression after being diagnosed with inflammatory bowel disease: a cohort study.

Abstract: Summary Background Studies have found that depression is more frequent in patients with inflammatory bowel disease (IBD) than the general population. Clinicians are now trying to pinpoint risk factors for psychological impairment in the IBD population. Aims To examine the demographic and phenotypic variables associated with the development of depression among a diverse cohort of IBD patients. We also sought to describe psychotropic therapy prescribed to IBD patients. Methods We conducted a retrospective cohort study including patients with Crohn's disease (CD) and ulcerative colitis (UC) without a prior psychiatric diagnosis and followed in the gastroenterology clinics of the private university hospital and public safety net hospital at a large academic centre in Miami (Florida). Predictive variables included demographic characteristics, IBD phenotype, exposure to IBD medications, history of a surgical stoma or seton placement, extra-intestinal manifestations, laboratory indices, aggressive disease and disease activity (based on imaging and endoscopic parameters). Proportional hazard regression models and stepwise Cox regression analysis were used for statistical analysis. Results Independent predictors of depression were female gender [HR: 1.3 (95% CI: 1.1–1.7), P = 0.01], aggressive disease [HR: 1.4 (95% CI: 1.02–1.9), P = 0.03] and active disease [HR: 1.5 (95% CI: 1.1–2.0), P = 0.04]. In the group that did develop a depressive disorder, 65% received pharmacologic therapy with one or more psychotropic agents. Conclusions We found female gender, aggressive disease and increased endoscopic/radiological activity to be independently associated with the development of depression in inflammatory bowel disease.

Extra-hepatic manifestations of autochthonous hepatitis E infection.

Abstract: SummaryBackground Autochthonous (locally acquired) hepatitis E is increasingly recognised in developed countries, and is thought to be a porcine zoonosis. A range of extra-hepatic manifestations of hepatitis E infection have been described, but have never been systematically studied. Aim To report the extra-hepatic manifestations of hepatitis E virus. Methods Retrospective review of data of 106 cases of autochthonous hepatitis E (acute n = 105, chronic n = 1). Results Eight (7.5%) cases presented with neurological syndromes, which included brachial neuritis, Guillain-Barre syndrome, peripheral neuropathy, neuromyopathy and vestibular neuritis. Patients with neurological syndromes were younger (median age 40 years, range 34–92 years, P = 0.048) and had a more modest transaminitis (median ALT 471 IU/L, P = 0.015) compared to cases without neurological symptoms [median age 64 years (range 18–88 years), median ALT 1135 IU/L]. One patient presented with a cardiac arrhythmia,twelve patients (11.3%) presented with thrombocytopenia, fourteen (13.2%) with lymphocytosis and eight (7.5%) with a lymphopenia, none of which had any clinical consequence. Serum electrophoresis was performed in 65 patients at presentation, of whom 17 (26%) had a monoclonal gammopathy of uncertain significance. Two cases developed haematological malignancies, acute myeloid leukaemia and duodenal plasmacytoma, 18 and 36 months after presenting with acute hepatitis E infection. Conclusions A range of extra-hepatic manifestations can occur with hepatitis E. Neurological and haematological features of hepatitis E infection are relatively frequent in this UK cohort, and result in significant morbidity which warrants further study.

Systematic review: Sprue-like enteropathy associated with olmesartan.

Abstract: SummaryBackground The onset of a sprue-like enteropathy in association with olmesartan therapy has been recently reported. Aims To perform a systematic review of the literature and describe three additional cases of olmesartan-associated enteropathy. Methods Electronic and manual bibliographic searches were performed to identify original reports in which subjects who were undertaking olmesartan developed a sprue-like enteropathy. Because of the scarcity of studies with adequate sample size, case series with less than 10 patients and case reports were also considered. Data extraction was performed independently by two reviewers. Results A total of 11 publications met our pre-defined inclusion criteria, for an overall number of 54 patients (including our series). Almost all patients presented with diarrhoea and weight loss. Normocytic normochromic anaemia and hypoalbuminaemia were the commonest laboratory defects at presentation. Antibody testing for coeliac disease was always negative. Variable degrees of duodenal villous atrophy were present in 98% of patients, while increased intra-epithelial lymphocytes were documented in only 65% of cases. After discontinuation of olmesartan, all reported patients achieved resolution of signs and symptoms. Conclusions Although the available evidence is limited, the olmesartan-associated sprue-like enteropathy may be considered as a distinct clinical entity, and should be included in the differential diagnosis when serological testing for coeliac disease is negative.