Crohn's disease (CD) is an incurable intestinal disorder in which the loss of immune tolerance to the commensal gut microbiota leads to chronic inflammation. The reason this occurs in specific individuals is unclear; however, a genetic predisposition is fundamental and relatives of patients with CD are at significant risk of developing the disease. Knowledge relating to the genetic loci that predispose to CD is accumulating, which raises the possibility of disease prediction and prevention in susceptible populations. However, the genetic basis of CD is complex and genotyping alone is likely to be insufficient to predict disease risk accurately. Specific physiological abnormalities associated with CD, such as increased intestinal permeability and raised faecal calprotectin, are also abnormal in some relatives of patients with CD. The combination of genotypic factors and biomarkers of risk makes the development of models of disease prediction a realistic possibility. Furthermore, enhanced understanding of the genotype and phenotype of the at-risk state in relatives of patients with CD allows the earliest stages in the pathogenesis of CD to be investigated and may allow intervention to prevent disease onset. This article reviews current knowledge of the at-risk phenotype in relatives of patients with CD and focuses on the implications for the design of future studies.

Iron deficiency anaemia (IDA) occurs in 2-5% of adult men and postmenopausal women in the developed world and is a common cause of referral to gastroenterologists. Gastrointestinal (GI) blood loss from colonic cancer or gastric cancer, and malabsorption in coeliac disease are the most important causes that need to be sought. DEFINING IRON DEFICIENCY ANAEMIA: The lower limit of the normal range for the laboratory performing the test should be used to define anaemia (B). Any level of anaemia should be investigated in the presence of iron deficiency (B). The lower the haemoglobin the more likely there is to be serious underlying pathology and the more urgent is the need for investigation (B). Red cell indices provide a sensitive indication of iron deficiency in the absence of chronic disease or haemoglobinopathy (A). Haemoglobin electrophoresis is recommended when microcytosis and hypochromia are present in patients of appropriate ethnic background to prevent unnecessary GI investigation (C). Serum ferritin is the most powerful test for iron deficiency (A).

Arthropathies are a major clinical problem in patients with inflammatory bowel disease (IBD). Often it is difficult to control the articular symptoms with the anti-inflammatory strategies used for IBD. Studies evaluating specific treatments aimed at articular manifestations in patients with IBD are rare. Although there has been considerable interest in the gut-joint axis over the last decade, the pathophysiological mechanisms driving IBD-associated arthropathy are still unknown. Recently, interest in the multidisciplinary approach to patients with IBD and arthropathy has been increasing. New research and clinical projects aimed at understanding the mechanisms of disease may advance the development of effective therapies. In this review, the pathophysiology of IBD-associated arthropathy is discussed, as well as clinical manifestations, the classification and current therapeutic strategies.

Unexplained chest pain is potentially attributable to gastro-oesophageal reflux disease (GORD) or oesophageal motility disorders. Reflux chest pain may occur without heartburn. We explored the response of unexplained chest pain to proton pump inhibitor (PPI) therapy in randomised clinical trials (RCTs), differentiating patients with and without objective evidence of GORD.

Past and ongoing therapeutic concepts for ulcerative colitis have only been moderately successful. A significant proportion of patients with ulcerative colitis will still have to undergo colectomy and overall half of the patients do not achieve sustained remission, leading to impairment of physical and mental health, social life, employment issues and sexual activity. Reluctance to treat patients early on with sufficiently potent drug regimens is obvious. Several popular misconceptions might have led to this situation. First, ulcerative colitis is still considered a more 'benign' disease than Crohn's disease. Furthermore, the general assumption is often that colectomy can 'cure' the disease. Mucosal healing as a therapeutic target has not been widely accepted. Finally, the use of antitumour necrosis factor antibodies in ulcerative colitis has been low because this treatment is considered to be less effective than in Crohn's disease. In the current review we try to disprove these misunderstandings by discussing relevant studies showing how harmful this disease can be and explaining why future studies targeting sustained suppression of inflammation could have an enormous impact on the natural course of the disease. Until these studies are available, we encourage physicians to intensify and maintain treatment until sustained remission and mucosal healing has been reached.

Omega (ω)-3 polyunsaturated fatty acids (PUFAs) are naturally occurring substances that are well tolerated and have been used extensively for the prevention of cardiovascular disease. More recently, ω-3 PUFAs have been recognised to have anticancer activity. There is also evidence suggesting improved efficacy and/or tolerability of conventional cancer chemotherapy when administered with ω-3 PUFAs. The purpose of this review is to (i) describe the mechanisms by which ω-3 PUFAs are thought to have antineoplastic activity, (ii) review published preclinical and clinical studies that support anti-colorectal cancer activity and (iii) summarise current clinical trials investigating the potential therapeutic role(s) of ω-3 PUFAs at different stages of colorectal carcinogenesis, from adenoma (polyp) prevention to treatment of established malignant disease and prevention of cancer recurrence.

Upper gastrointestinal bleeding (UGIB), especially peptic ulcer bleeding, remains one of the most important cause of hospitalisation and mortality world wide. In Asia, with a high prevalence of Helicobacter pylori infection, a potential difference in drug metabolism, and a difference in clinical management of UGIB due to variable socioeconomic environments, it is considered necessary to re-examine the International Consensus of Non-variceal Upper Gastrointestinal Bleeding with emphasis on data generated from the region. The working group, which comprised experts from 12 countries from Asia, recommended the use of the Blatchford score for selection of patients who require endoscopic intervention and which would allow early discharge of patients at low risk. Patients' comorbid conditions should be included in risk assessment. A pre-endoscopy proton pump inhibitor (PPI) is recommended as a stop-gap treatment when endoscopy within 24 h is not available. An adherent clot on a peptic ulcer should be treated with endoscopy combined with a PPI if the clot cannot be removed. Routine repeated endoscopy is not recommended. High-dose intravenous and oral PPIs are recommended but low-dose intravenous PPIs should be avoided. COX-2 selective non-steroidal anti-inflammatory drugs combined with a PPI are recommended for patients with very high risk of UGIB. Aspirin should be resumed soon after stabilisation and clopidogrel alone is no safer than aspirin plus a PPI. When dual antiplatelet agents are used, prophylactic use of a PPI reduces the risk of adverse gastrointestinal events.

The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of 'Quality Care: service standards for the healthcare of people with IBD' in 2009. The introduction of the Montreal classification for Crohn's disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn's disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn's and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).

Multimodal treatment options for advanced gastroenteropancreatic neuroendocrine tumours (NET) of jejunum/ileum and of pancreatic origin are reviewed. Current topics being discussed are: European Neuroendocrine Tumour Society 2006/7, American Joint Cancer Committee/Union Internationale Contre le Cancer 2009 and WHO 2010 recommendations for grading and staging of NET; surgery of the primary tumour in distant metastasised disease; surgery of metastatic liver disease and impact on survival; somatostatin analogues for symptom control and for tumour control; selective internal radiation therapy with 90Y-microspheres as novel local ablative therapy in liver metastases; peptide receptor radionuclide therapy; novel chemotherapy regimens (eg, temozolomide) and novel targeted therapies (eg, sunitinib and everolimus).

To propose an improvement on the current classification of renal dysfunction in cirrhosis. Clinicians caring for patients with cirrhosis recognize that the development of renal dysfunction is associated with significant morbidity and mortality. While most cases of renal dysfunction in cirrhosis are functional in nature, developed as a result of changes in haemodynamics, cardiac function, and renal auto-regulation, there is an increasing number of patients with cirrhosis and structural changes in their kidney as a cause of renal dysfunction. Therefore, there is a need for a newer classification to include both functional and structural renal diseases.

This consensus report of the EGILS (European Gastro-Intestinal Lymphoma Study) group includes recommendations on the management of gastric extranodal marginal zone B-cell lymphoma of MALT. They are based on data from the literature and on intensive discussions and votings of the experts during their annual meetings.

Pathologist's observations have remained central to the evolution of the field of non-alcoholic fatty liver disease, even with the advent of increasingly effective non-invasive markers of advanced fibrosis. As the field matures, the role of pathology has also shifted from being largely descriptive to being confirmatory and diagnostic, as well as providing semi-quantitative evaluation of specific findings, particularly in therapeutic interventional trials. Some newly appreciated histopathological findings will be discussed in this review.

Achalasia is an esophageal motility disorder of unknown cause, characterised by aperistalsis of the esophageal body and impaired lower esophageal sphincter relaxation. Patients present at all ages, primarily with dysphagia for solids/liquids and bland regurgitation. The diagnosis is suggested by barium esophagram or endoscopy and confirmed by esophageal manometry. Achalasia cannot be cured. Instead, our goal is to relieve symptoms, improve esophageal emptying and prevent the development of megaesophagus. The most successful therapies are pneumatic dilation and surgical myotomy. The advantages of pneumatic dilation include an outpatient procedure, minimal pain, return to work the next day, mild if any GERD, and can be performed in any age group and even during pregnancy. Pneumatic dilation does not hinder future myotomy, and all cost analyses find it less expensive than Heller myotomy. Laparoscopic myotomy with a partial fundoplication has the advantage of being a single procedure, dysphagia relief is longer at the cost of more troubling heartburn, and a myotomy may be more effective treatment in adolescents and younger adults, especially men. Over a two year horizon, the clinical success of pneumatic dilation and laparoscopic myotomy are comparable in a recent large European randomised trial. The prognosis for achalasia patients to return to near-normal swallowing and good quality of life are excellent, but few are "cured" with a single treatment and intermittent "touch up" procedures may be required.

For two decades the scientific community has sought to understand why some people clear hepatitis C virus (HCV) and others do not. Recently, several large genome-wide association studies have identified single nucleotide polymorphisms (SNPs) linked to interferon lambda 3 (IFNλ3) that are associated with the spontaneous resolution and successful treatment of HCV infection. These observations are generating intense research activity; the hope is that IFNλ3 genetic variants may serve as important predictive biomarkers of treatment outcome and offer new insights into the biological pathways involved in viral control. A pharmacogenomic treatment approach for HCV can now be envisaged, with the incorporation of host genetic variants into a predictive treatment algorithm with other factors. The SNPs associated with the clinical outcome of HCV infection are located some distance from the IFNλ3 gene itself, and causal genetic variants have yet to be clearly defined. Locating these causal variants, mapping in detail the IFNλ3 signalling pathways and determining the downstream genetic signature so induced will clarify the role of IFNλ3 in the pathogenesis of HCV. Clinical studies assessing safety and efficacy in the treatment of HCV with exogenous IFNλ3 are currently underway. Early results suggest that IFNλ3 treatment inhibits HCV replication and is associated with a limited side effect profile. However, hepatotoxicity in both healthy volunteers and HCV-infected patients has been described. This review discusses the genetic studies that link IFNλ3 to both the spontaneous resolution and treatment-induced clearance of HCV and the potential impact of this in clinical practice, the biology of IFNλ3 as currently understood and how this may impact on HCV infection, and describes the early studies that assess the role of this cytokine in the treatment of patients with HCV.

Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn's disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn's disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (IL23R, IL12B, JAK2, TYK2 and STAT3), IL10, IL1R2, REL, CARD9, NKX2.3, ICOSLG, PRDM1, SMAD3 and ORMDL3. The evolving genetic architecture of IBD has furthered our understanding of disease pathogenesis. For Crohn's disease, defective processing of intracellular bacteria has become a central theme, following gene discoveries in autophagy and innate immunity (associations with NOD2, IRGM, ATG16L1 are specific to Crohn's disease). Genetic evidence has also demonstrated the importance of barrier function to the development of ulcerative colitis (HNF4A, LAMB1, CDH1 and GNA12). However, when the data are analysed in more detail, deeper themes emerge including the shared susceptibility seen with other diseases. Many immune-mediated diseases overlap in this respect, paralleling the reported epidemiological evidence. However, in several cases the reported shared susceptibility appears at odds with the clinical picture. Examples include both type 1 and type 2 diabetes mellitus. In this review we will detail the presently available data on the genetic overlap between IBD and other diseases. The discussion will be informed by the epidemiological data in the published literature and the implications for pathogenesis and therapy will be outlined. This arena will move forwards very quickly in the next few years. Ultimately, we anticipate that these genetic insights will transform the landscape of common complex diseases such as IBD.

Polymorphisms in NOD2, encoding an intracellular pattern recognition receptor, contribute the largest fraction of genetic risk for Crohn's disease among the >40 risk loci identified so far. Autophagy plays a prominent role in the innate immune response towards intracellular bacteria. The discovery of the autophagy genes ATG16L1 and IRGM as risk factors for Crohn's disease turned autophagy into the spotlight in inflammatory bowel disease (IBD). Remarkably, NOD2 has recently been identified as a potent autophagy inducer. A physical interaction of NOD2 and ATG16L1 appears to be required for autophagic clearance of intracellular pathogens. Moreover, Crohn's disease-associated NOD2 and ATG16L1 variants exhibit a defect in the induction of an autophagic response and hence predict autophagy as a key converging mechanism that leads to Crohn's disease. Another pathway that is closely intertwined with autophagy and mutually cross-regulated is the unfolded protein response (UPR), which is induced by endoplasmic reticulum (ER) stress. Genes involved in the UPR (XBP1, ORMDL3) have also been genetically associated with Crohn's disease and ulcerative colitis. Moreover, the intestinal epithelium at the interface between host and microbe appears particularly affected by IBD-associated hypomorphic function of autophagy and the UPR. The functional convergence of main genetic risk factors for IBD on these innate immune pathways has hence important implications for the host's interaction with the microbiota. Moreover, the genetic convergence on these molecular mechanisms may open novel therapeutic options for IBD that deserve further exploration.

Insulin resistance and diabetes are inextricably linked to chronic hepatitis C. Our understanding of this relationship continues to improve. This review focuses on the molecular mechanisms relating insulin resistance to hepatitis C with a subsequent overview of the consequences of hepatitis C-associated insulin resistance and diabetes, as well as perspectives for future management.

Colorectal cancer (CRC) is a multifactorial disease with both environmental and genetic factors contributing to its development. The incidence of CRC is increasing year by year in Japan. Patients with CRC in advanced stages have a poor prognosis, but detection of CRC at earlier stages can improve clinical outcome. Therefore, identification of epidemiologial factors that influence development of CRC would facilitate the prevention or early detection of disease.