Inflammatory neuropathy of the enteric nervous system is emerging as an important topic in the field of neurogastroenterology. Enteric ganglionitis can be either primary or secondary to a wide array of diseases (i.e., paraneoplastic, infectious, and neurological disorders) and is characterized by a dense infiltrate of inflammatory/immune cells mainly confined to the neural microenvironment. The clinical picture reflects the involved segment of the gastrointestinal tract (achalasia, gastroparesis, pseudo-obstruction, and megacolon). In these settings, symptoms may develop either acutely (frequently after a flulike episode in otherwise previously healthy individuals) or more slowly (e.g., in paraneoplastic syndromes). The inflammatory/immune response in enteric ganglionitis leads to neuronal dysfunction and degeneration over time and sometimes results in a complete loss of enteric neurons. The diagnosis of enteric ganglionitis is supported by detection of circulating antineuronal antibodies against select molecular targets, including Hu and Yo proteins, neurotransmitter receptors, and ion channels. Potential mechanisms involved in neuronal dysfunction include viral antigen expression in the enteric neural environment, molecular mimicry (onconeural antigens), and the role exerted by cellular and humoral autoimmunity. A short course of steroid or other immunosuppressive therapy has been shown to be helpful in the treatment of these conditions. This feature reinforces the concept of a cause/effect relationship of the immune-mediated insult damaging the enteric innervation. An increased awareness of the clinical features and the immunologic and neurodegenerative mechanisms of these forms of peripheral neuropathy is important to correctly diagnose this problem during the early stages of the disease process and to provide appropriate immunosuppressive therapies.

Traditionally, randomized controlled trials (RCTs) have attempted to show the superiority of one intervention over another. However, when effective treatment already exists, it is sometimes more useful to prove that an intervention is equivalent, or at least not inferior, to the standard of care. Our aim was to determine whether claims of equivalency in digestive diseases trials are supported by the evidence.

Patients with ulcerative colitis and Crohn's colitis face an increased lifetime risk of developing colorectal cancer. Factors associated with increased risk include long duration of colitis, extensive colonic involvement, primary sclerosing cholangitis, a family history of colorectal cancer, and, according to some studies, early disease onset and more severely active inflammation. Although prophylactic proctocolectomy can essentially eliminate the risk of cancer, most patients and their physicians opt instead for a lifelong program of surveillance. This entails regular medical follow-up, management with antiinflammatory and putative chemopreventive agents, and periodic colonoscopic examinations combined with extensive biopsy sampling throughout the colon. The main objective of regular colonoscopy is to detect neoplasia at a surgically curative and preferably preinvasive stage, i.e., dysplasia. An initial screening colonoscopy should be performed 7-8 years from disease onset or immediately in patients with primary sclerosing cholangitis. Surveillance should then continue annually or biennially so long as no dysplasia is found or suspected. Biopsy specimens are graded pathologically as negative, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, or invasive cancer. The diagnosis and grading of dysplasia can be very challenging and should be confirmed by an expert pathologist whenever intervention or a change in management is contemplated. If 1 or more biopsy specimens are indefinite for dysplasia, colonoscopy intervals should be reduced. A patient with low- or high-grade dysplasia found in a discrete adenoma-like polyp, but nowhere else, can be safely managed with polypectomy and accelerated surveillance. However, dysplasia of any grade found in an endoscopically nonresectable polyp and high-grade dysplasia found in flat mucosa are both strong indications for proctocolectomy. Evidence further suggests that the same may be true even of low-grade dysplasia in flat mucosa. Chromoendoscopy holds promise for facilitating the endoscopic detection of neoplasia. The clinical application of newer molecular methods to detect neoplasia, particularly gene microarrays and stool DNA testing, also deserve further study.

Crohn's disease, ulcerative colitis, and pouchitis are caused by overly aggressive immune responses to a subset of commensal (nonpathogenic) enteric bacteria in genetically predisposed individuals. Clinical and experimental studies suggest that the relative balance of aggressive and protective bacterial species is altered in these disorders. Antibiotics can selectively decrease tissue invasion and eliminate aggressive bacterial species or globally decrease luminal and mucosal bacterial concentrations, depending on their spectrum of activity. Alternatively, administration of beneficial bacterial species (probiotics), poorly absorbed dietary oligosaccharides (prebiotics), or combined probiotics and prebiotics (synbiotics) can restore a predominance of beneficial Lactobacillus and Bifidobacterium species. Current clinical trials do not fulfill evidence-based criteria for using these agents in inflammatory bowel diseases (IBD), but multiple nonrigorous studies and widespread clinical experience suggest that metronidazole and/or ciprofloxacin can treat Crohn's colitis and ileocolitis (but not isolated ileal disease), perianal fistulae and pouchitis, whereas selected probiotic preparations prevent relapse of quiescent ulcerative colitis and relapsing pouchitis. These physiologic approaches offer considerable promise for treating IBD, but must be supported by rigorous controlled therapeutic trials that consider clinical disease before their widespread clinical acceptance. These agents likely will become an integral component of treating IBD in combination with traditional anti-inflammatory and immunosuppressive agents.

Surgery improves the quality of life in patients with Crohn's disease (CD) and cures patients with chronic ulcerative colitis (CUC). There are several surgical controversies primarily involving techniques and long-term outcomes. Some debates are long standing; whether to perform a double-stapled ileal pouch-anal anastomosis (IPAA) or a mucosectomy and hand-sewn anastomosis, and whether to divert or not to divert in patients with CUC undergoing an IPAA. Other issues are more recent, such as the effects of age, pregnancy, pouch salvage, and laparoscopic IPAA. In patients with Crohn's disease the anastomosis technique, the management of perianal disease, and the role of laparoscopic surgery are topics of debate. This review shows the current concepts and controversies in the surgical management of patients with CUC or CD.

Infliximab, the chimeric monoclonal immunoglobulin (Ig)G1 antibody to tumor necrosis factor (TNF) has changed our therapy of Crohn's disease. Infliximab is indicated in refractory luminal and fistulizing Crohn's disease. In patients with luminal disease, a single intravenous (i.v.) dose of 5 mg/kg is efficacious; in fistulizing disease, an i.v. loading therapy of 5 mg/kg at weeks 0, 2, and 6 is advocated. Because the majority of patients will relapse if not re-treated, a long-term strategy is necessary. The optimal long-term approach is systematic re-treatment with 5 mg/kg every 8 weeks. Episodic therapy on relapse also is possible but is less efficacious and frequently is associated with problems resulting from the formation of antibodies to infliximab (ATI). If treatment is episodic, maintenance therapy with immunosuppression (azathioprine [AZA]/6-mercaptopurine [6-MP] or methotrexate) is mandatory. Trial data suggest that systematic maintenance with 8 weekly doses of infliximab decreases the rate of complications, hospitalizations, and surgeries. These effects probably are achieved thanks to thorough healing of the bowel. Infliximab also is indicated in treating corticosteroid-dependent Crohn's disease and extraintestinal manifestations of Crohn's disease. There are no data yet that support its use as first-line therapy. The data in ulcerative colitis (UC) are conflicting and we should await the results of 2 large controlled trials (ACT1 and ACT2) to position infliximab in the treatment of UC. Other anti-TNF strategies have been less effective than infliximab in the treatment of IBD until now. The results with thalidomide are promising but much more research into small molecules inhibiting TNF and other proinflammatory cytokines is necessary. Safety problems with antibody treatment mainly concern immunogenicity leading to infusion reactions, loss of response, and serum sickness-like delayed infusion reactions. The rate of opportunistic infections is increased mainly in patients treated concomitantly with immunosuppression. Other adverse events associated with anti-TNF strategies are demyelinating disease and worsening of congestive heart failure. Malignancy rates in patients treated with anti-TNF strategies do not seem to be increased.

There continue to be evolutionary changes in the management of ulcerative colitis despite the fact that, aside from a variety of aminosalicylate formulations, no new therapies have been approved over the past few decades. Nevertheless, debates continue regarding the optimization of treatment with aminosalicylates and the short- and long-term benefits of immunomodulation in ulcerative colitis. This article focuses on the most recent clinical studies pertaining to the management of ulcerative colitis and explores both the advances and controversies pertaining to aminosalicylate therapy, corticosteroids, cyclosporine, and the purine antimetabolites. Novel therapeutic approaches--including preliminary experience with biological therapies directed at tumor necrosis factor and other cytokines, adhesion molecules, growth factors, and probiotics--will be reviewed. Recent data regarding potential chemoprevention in long-standing ulcerative colitis and management of postoperative complications and pouchitis will also be discussed.

The medical therapy of Crohn's disease has improved considerably in recent years. In large part, this is due to the introduction of new efficacious agents, both "biologics" and traditional small molecules. Further study of older drugs has also advanced our ability to devise the optimum approach to individual Crohn's disease patients by better clarifying the benefits, adverse effects, and means to optimize doses of established medications. In this review, we present an evidence-based approach to the medical management of active Crohn's disease, Crohn's disease in remission, and perianal Crohn's disease that emphasizes recent advances that have come from the results of randomized controlled clinical trials.

A correct diagnosis, adequate assessment of disease activity, avoidance of surgery by endoscopic interventions, and effective cancer surveillance make endoscopy crucial in the management of inflammatory bowel diseases (IBDs). Impressive technical developments of several endoscopic techniques over the past few decades have allowed a detailed visual impression of the affected gut and enable tissue sampling and various therapeutic interventions. Here we propose guidelines for endoscopy in inflammatory bowel disease, and review all currently available endoscopic techniques relevant to the proper treatment of IBD patients.

Inflammatory bowel diseases (Crohn's disease and ulcerative colitis) primarily affect young adults, but in 15%-25% of cases, the initial disease starts in childhood. Many aspects of inflammatory bowel disease, including initial evaluation, nutritional support, medical and surgical intervention, and the direction of future research, are encountered in both adult and pediatric patients. However, it is important to delineate issues specific to pediatric patients, especially growth velocity impairment, derangements in and treatment of abnormal bone mineralization, and transitional care issues; the lack of extensive randomized, controlled pediatric therapeutic trials is also a concern. This article reviews the epidemiology of pediatric inflammatory bowel disease incidence and prevalence worldwide, clinical issues (including impairments of growth velocity and bone density), diagnostic and therapeutic interventions, and psychosocial issues unique to pediatric patients. Future research directions defined by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and opportunities provided by existing pediatric research databases are highlighted.

Crohn's disease and ulcerative colitis result from an inappropriate response of the mucosal immune system to the normal enteric flora in a genetically susceptible individual. During the past decade, exciting progress has been made in our understanding of the contribution of genetics to inflammatory bowel disease susceptibility and phenotype. This article reviews recent advances in the genetics of inflammatory bowel disease and explores how they might impact on clinical practice. Current knowledge of the genetic basis for disease susceptibility, phenotype, and response to therapy is explored and the factors currently limiting the translation of this knowledge to clinical practice is discussed.

This document presents the official recommendations of the American Gastroenterological Association (AGA) on Hemorrhoids. It was approved by the Clinical Practice Committee on January 8, 2004, and by the AGA Governing Board on February 13, 2004.

The development and dissemination of sophisticated detection technologies have recently exposed the high prevalence of preinvasive colorectal neoplasia in the adult U.S. population. Although cancer screening and surveillance provide opportunities for risk stratification, they achieve risk reduction only when coupled with effective interventions. This review surveys the lead compounds for colorectal cancer prevention and the measures by which they may be prioritized for clinical testing. Clinical trials remain the rate-limiting step in agent development, and novel trial designs are needed to hasten agent identification and testing for cancer prevention. Innovative research models include the nesting of prevention end points within cancer treatment trials and within trials testing promising preventive compounds intended for nononcologic indications.