The appropriate treatment of patients with fistulas in the setting of Crohn's disease requires a knowledge of the specific medical and surgical literature of fistulizing Crohn's. The patient with symptomatic fistulizing Crohn's disease may respond differently to specific medical therapy than a patient with symptomatic obstructing Crohn's disease. Certain medications that are useful for the treatment of patients with obstructive Crohn's disease may not be helpful in the treatment of fistulas in patients with fistulizing Crohn's disease (e.g., corticosteroids and mesalamine); in fact, some medications are believed to be detrimental (e.g., corticosteroids). Few studies have been performed to assess the efficacy of specific medications on fistulas directly. To date, there has been only one published prospective randomized controlled trial that was designed to assess the efficacy and safety of a specific medication on fistulas in patients with Crohn's disease; it showed clinical efficacy over placebo in a statistically significant manner. The judicious use of surgery remains an integral part of the management of certain presentations of fistulizing Crohn's disease, and the appropriate integration of surgical and medical therapy is of paramount importance in the management of these patients. This review provides an overview of pertinent medical and surgical literature as it pertains to management of patients with fistulizing Crohn's disease.

Circadian rhythms play a major role in regulating the digestive systems of many organisms. Cell proliferation, migration, differentiation, and even structure vary as a function of time of day in many different digestive organs (i.e., stomach, gut, liver, and pancreas) and cell types, resulting in regionally specific temporal variations in protein and gene expression. Feeding and light set the hands of the digestive clock(s). However, the clockwork has a genetic basis. During the last 10 years, new developments have emerged in our understanding of how cells keep time. Surprisingly, clock genes in mammals are expressed not only in specialized time keepers in the brain, but also in peripheral organs, suggesting that the ability to keep time may also belong to cells within the digestive system. This article reviews several classic examples of circadian variation in the digestive system, with an emphasis on rhythms in cell proliferation, function, and structure. It also briefly summarizes several new ideas about how cells in the brain and possibly the digestive system keep time.

By inhibiting prostaglandin synthesis, nonsteroidal anti-inflammatory drugs (NSAIDs) compromise gastroduodenal defense mechanism including blood flow and mucus/bicarbonate secretion. This has led to NSAIDs being the most widely reported drug cause of adverse events. While NSAIDs also cause dyspepsia, inhibition of prostaglandin synthesis may reduce this from even higher levels that would otherwise prevail and mask ulcer-related dyspepsia, making anticipatory management difficult. On average, the risk of ulcer complications increases 4-fold, resulting in 1.25 additional hospitalizations per 100 patient-years according to one estimate. Older patients, those with a past history, and those taking anticoagulants or corticosteroids are at higher risk. Risk is dose dependent and is lower with ibuprofen at low doses than with other NSAIDs. It is unlikely that Helicobacter pylori increases the risk, and under some circumstances it may be protective. Selective inhibitors of the inducible cyclooxygenase 2 spare gastric mucosal prostaglandin synthesis and do not damage the gastric mucosa. Their place in therapy, compared with use of misoprostol or proton pump inhibitors, is currently emerging. Future competitors may include nitric oxide-donating, zwitterionic, or R-enantiomer NSAIDs.

Nitric oxide (NO) is now recognized as an important modulator of an enormous number of physiological processes, ranging from blood pressure regulation to neuronal transmission to penile erectile function. In the gastrointestinal tract, NO also participates in many physiological and pathophysiological processes. In this review, we summarize the contribution made by NO to the ability of the gastrointestinal mucosa to resist injury induced by luminal toxins and to defend against microbial invasion. We also review some of the main features of NO chemistry and the potential of NO as a target for new drugs to treat gastrointestinal disorders.

The published risk of adenocarcinoma in the setting of Barrett's esophagus (BE) varies. Publication bias, the selective reporting of studies featuring positive or extreme results, may result in overestimation of this cancer risk in the literature. The aim of this study was to assess those publications reporting a cancer risk in BE for evidence of publication bias.

Celiac disease is a gluten-sensitive enteropathy, characterized by villous atrophy, which is reversed by gluten withdrawal. A minority of patients with celiac-like enteropathy are resistant to gluten-free diet, so-called refractory sprue, or unclassified sprue. Refractory sprue is a diagnosis of exclusion; all other causes of a celiac-like enteropathy must be eliminated before a diagnosis of refractory sprue can be made. Recent evidence suggests that refractory sprue comprises a heterogenous group of patients with diverse underlying causes. A small proportion of these patients seem to have an adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies. However, a larger group of patients with refractory sprue now seem to have a cryptic intestinal T-cell lymphoma, characterized by the presence of phenotypically abnormal, monoclonal intraepithelial lymphocytes, despite benign cytology. Current therapeutic options include nutritional support and immunosuppressive therapy, but response is variable. The prognosis of refractory sprue may be poor; patients may die of severe malabsorption, or through synchronous or metachronous development of an enteropathy-associated T-cell lymphoma. Based on this recent evidence, patients with refractory sprue should be screened for antienterocyte antibodies and have T-cell receptor and monoclonal antibody studies performed; this could facilitate identification of cases of adult-onset autoimmune enteropathy and those of cryptic T-cell lymphoma. Moreover, early recognition of the malignant nature of the intestinal infiltrate in some cases of refractory sprue could permit the development of novel chemotherapeutic regimens for this condition.

Our knowledge of celiac disease pathogenesis has recently made rapid progress. The disorder is now considered the result of a complex interplay of intrinsic (genetic) and variable extrinsic (environmental) factors that explain the wide spectrum of clinical manifestations ranging from asymptomatic to severe malabsorption. Gluten peptides are efficiently presented by celiac disease-specific HLA-DQ2- and HLA-DQ8-positive antigen-presenting cells, and thus drive the immune response, predominantly in the connective tissue of the lamina propria. Tissue transglutaminase, which has been identified as the highly specific endomysial autoantigen, is released from cells during inflammation. It may potentiate antigen presentation by HLA-DQ2 and HLA-DQ8 by deamidating or cross-linking gluten peptides. The result is lamina propria T-cell activation and mucosal transformation by activated intestinal fibroblasts. In the future, manipulation of the gut-associated lymphoid tissue may allow reduced sensitivity or even generate oral tolerance to gluten. Long-standing untreated celiac disease, even if clinically silent, predisposes for other autoimmune diseases. Therefore, population screening for immunoglobulin A antibodies to tissue transglutaminase seems justified.

Chronic hepatitis C virus infection is common in the United States with an estimated prevalence of 2.7 million persons. Fortunately, the incidence of new infections has markedly declined in recent years and the natural history of chronic hepatitis usually only results in significant progression after several decades of infection. However, the majority of chronically infected patients acquired their infections more than 20 years ago; these patients with long-standing chronic hepatitis are now presenting in increasing numbers with decompensated cirrhosis and the need for liver transplantation. Cirrhosis caused by chronic hepatitis C is now the most common indication for liver transplantation. Interferon monotherapy became clinically available 10 years ago but resulted in sustained improvement in liver disease and durable loss of detectable virus in fewer than 10% of treated patients. The recent use of the combination of interferon with the nucleoside analogue ribavirin for 6-12 months results in a sustained virological response in 30%-40% of previously untreated patients. The response to this combination therapy is also excellent in patients who had initially responded to interferon monotherapy and later relapsed. Furthermore, some recent studies suggest that a small proportion of patients who failed to respond to a prior course of interferon (primarily noncirrhotic patients with low levels of virus and genotypes other than 1) may also benefit from retreatment with this combination.