Adult eosinophilic gastroenteritis and hypereosinophilic syndromes

Eosinophilic gastroenteritis (EGE) in the adult is a distinctive pathologically-based disorder characterized by an eosinophil-predominant mucosal inflammatory process. Most often,the disorder is detected during endoscopic investigation for abdominal pain or diarrhea. Other causes of gastric and intestinal mucosal eosinophilia require exclusion,including parasitic infections and drug-induced causes. Occasionally,the muscle wall or serosal surface may be involved. EGE appears to be more readily recognized,in large part,due to an evolution in the imaging methods used to evaluate abdominal pain and diarrhea,in particular,endoscopic imaging and mucosal biopsies. Def inition of EGE,however,may be diffi cult,as the normal ranges of eosinophil numbers in normal and abnormal gastric and intestinal mucosa are not well standardized. Also,the eosinophilic inflammatory process may be either patchy or diffuse and the detection of the eosinophilic infiltrates may vary depending on the method of biopsy fixation. Treatment has traditionally focused on resolution of symptoms,and,in some instances,eosinophil quantification in pre-treatment and post-treatment biopsies. Future evaluation and treatment of EGE may depend on precise serological biomarkers to aid in defi nition of the long-term natural history of the disorder and its response to pharmacological or biological forms of therapy.

Intestinal lymphangiectasia in adults

Intestinal lymphangiectasia in the adult may be characterized as a disorder with dilated intestinal lacteals causing loss of lymph into the lumen of the small intestine and resultant hypoproteinemia, hypogamma-globulinemia, hypoalbuminemia and reduced number of circulating lymphocytes or lymphopenia. Most often, intestinal lymphangiectasia has been recorded in children, often in neonates, usually with other congenital abnormalities but initial def inition in adults including the elderly has become increasingly more common. Shared clinical features with the pediatric population such as bilateral lower limb edema, sometimes with lymphedema, pleural effusion and chylous ascites may occur but these reflect the severe end of the clinical spectrum. In some, diarrhea occurs with steatorrhea along with increased fecal loss of protein, reflected in increased fe- cal alpha-1-antitrypsin levels, while others may present with iron def iciency anemia, sometimes associated with occult small intestinal bleeding. Most lymphangiectasia in adults detected in recent years, however, appears to have few or no clinical features of malabsorption. Diagnosis remains dependent on endoscopic changes confirmed by small bowel biopsy showing histological evidence of intestinal lymphangiectasia. In some, video capsule endoscopy and enteroscopy have revealed moreextensive changes along the length of the small intes- tine. A critical diagnostic element in adults with lym- phangiectasia is the exclusion of entities (e.g. malignancies including lymphoma) that might lead to obstruction of the lymphatic system and "secondary" changes in the small bowel biopsy. In addition, occult infectious (e.g. Whipple's disease from Tropheryma whipplei) or in? am- matory disorders (e.g. Crohn's disease) may also present with profound changes in intestinal permeability and protein-losing enteropathy that also require exclusion. Conversely, rare B-cell type lymphomas have also been described even decades following initial diagnosis of intestinal lymphangiectasia. Treatment has been historically def ined to include a low fat diet with medium-chain triglyceride supplementation that leads to portal venous rather than lacteal uptake. A number of other pharma- cological measures have been reported or proposed but these are largely anecdotal. Finally, rare reports of localized surgical resection of involved areas of small intestine have been described but follow-up in these cases is often limited. 2011 Baishideng. All rights reserved.

Tropheryma whipplei infection

Whipple's disease was initially described in 1907. Over the next century, the clinical and pathological features of this disorder have been better appreciated. Most often, weight loss, diarrhea, abdominal and joint pain occur. Occasionally, other sites of involvement have been documented, including isolated neurological disease, changes in the eyes and culture-negative endocarditis. In the past decade, the responsible organism Tropheryma whipplei has been cultivated, its genome sequenced and its antibiotic susceptibility defined. Although rare, it is a systemic infection that may mimic a wide spectrum of clinical disorders and may have a fatal outcome. If recognized, prolonged antibiotic therapy may be a very successful form of treatment.

Intraductal papillary mucinous neoplasms and other pancreatic cystic lesions

Pancreatic cystic neoplasms are being increasingly recognized, even in the absence of symptoms, in large part, due to markedly improved imaging modalities such as magnetic resonance imaging (MRI)/magnetic resonance cholangio pancreatography (MRCP) and computer tomography (CT) scanning. During the past 2 decades, better imaging of these cystic lesions has resulted in definition of different types, including pancreatic intraductal papillary mucinous neoplasms (IPMN). While IPMN represent only a distinct minority of all pancreatic cancers, they appear to be a relatively frequent neoplastic form of pancreatic cystic neoplasm. Moreover, IPMN have a much better outcome and prognosis compared to pancreatic ductal adenocarcinomas. Therefore, recognition of this entity is exceedingly important for the clinician involved in diagnosis and further evaluation of a potentially curable form of pancreatic cancer.

Use of the Crohn's disease activity index in clinical trials of biological agents

The Crohn's disease activity index(CDAI) has been commonly used to assess the effects of treatment with different agents in Crohn's disease(CD).However these studies may be compromised,if the results compared to a placebo or standard therapy group(in the absence of a placebo) substantially differ from the expected response.In addition,significan concerns have been raised regarding the reliability and validity of the CDAI.Reproducibility of the CDAI may be limited as significant inter-observer error has been recorded,even if measurements are done by experienced clinicians with expertise in the diagnosis and treatment of CD.Finally,many CDAI endpoints are open to subjective interpretation and have the potential for manipulation.This is worrisome as there is the potential for significant financial gain if the results of a clinical trial appear to provide a positive result.Physicians caring for patients should be concerned about the positive results in clinica trials that are sponsored by industry,even if the trials involve respected centers and the results appear in highly ranked medical journals.

Long-term natural history of Crohn’s disease

Crohn’s disease is a chronic inflammatory granulomatous process that usually involves different sites in the intestinal tract. Genetic and environmental factors are thought to play a role in its etiology and pathogenesis. The disorder has a heterogeneous clinical expression and data from tertiary care settings have documented its female predominance, occasional familial nature, and high rate of stricture formation and penetrating disease. It may appear from early childhood to late adulthood, although over 80% are currently diagnosed before age 40 years, usually with terminal ileal and colonic involvement. Several studies have now shown differences in phenotypic clinical expression depending on the initial age at diagnosis, with pediatric-onset disease being more severe and more extensive with more involvement of the upper gastrointestinal tract compared to adult-onset disease. In addition, long- term studies from these tertiary care settings have documented that the disorder may evolve with time into a more complex disease with stricture formation and penetrating disease complications (i.e. fistula and abscess). Although prolonged remission with no evidence of inflammatory disease may occur, discrete periods of symptomatic and active granulomatous inflammatory disease may re-appear over many decades. Long-term studies on the natural history have also suggested that discrete events (or agents) may precipitate this granulomatous inflammatory process.

Venous thromboembolism with inflammatory bowel disease

Venous thrombosis and thromboembolism appear to be increased in patients with inflammatory bowel disease. Although several acquired and genetic risk factors are known, about half that develop a thromboembolic event have no identifiable risk factor. Control of the inflammatory process is thought to be the key factor in risk reduction for thrombotic events. Prophylactic use of anticoagulants is not universally recommended, but possible use should be reviewed in an individual patient after evaluation of the risks, such as hemorrhage, compared to potential benefits. Particular consideration should be given if there has been a prior thrombotic event, if hospitalization will require surgery, or if an underlying coagulation disorder is present.

Segmental colitis associated with diverticulosis syndrome

An inflammatory process that involves the sigmoid colonic segment associated with diverticular disease(SCAD) appears to be a distinct clinical and pathological disorder.It has been described in older adults,often presenting with rectal bleeding.Most of the patients seem to respond to treatment only with a 5-aminosalicylate,but some spontaneously resolve with no treatment.Endoscopic evaluation usually shows a non-specific inflammatory process localized in the sigmoid colon alone that may resolve completely with histologically normal colonic mucosa.Repeated symptomatic events with discrete episodes of segmental colitis may occur,but most patients have an entirely benign clinical course.Definition of the underlying molecular events that occur with SCAD may be critically important in understanding the critical elements present in a colonic inflammatory process that can completely resolve without pharmacological or biological treatment.

Heterogeneity of colorectal adenomas, the serrated adenoma, and implications for screening and surveillance

Current algorithms for screening and surveillance for colon cancer are valuable, but may be limited by the underlying nature of the targeted neoplastic lesions. Although part of the success of adenoma removal relates to interruption of so-called "adenoma-carcinoma sequence", an alternate serrated pathway to colon cancer may pose difficulties with the ultimate results achieved by traditional colonoscopic methods. The endpoint carcinoma in this unique pathway may be derived from a dysplastic serrated adenoma. These tend to be located primarily in the right colon, especially in females, and are frequently associated with co-existent colon cancer. Unfortunately, however, there are few, if any, other identifiable risk factors, including age or family history of colon polyps or colon cancer. Moreover, this alternate serrated pathway may itself also be quite biologically heterogeneous as reflected in sessile serrated adenomas (SSA) with virtually exclusive molecular signatures defined by the presence of either BRAF or KRAS mutations. Screening algorithms in the future may need to be modified and individualized, depending on new information that likely will emerge on the natural history of these biologically heterogeneous lesions that differs from traditional adenomatous polyps.

Crypt region localization of intestinal stem cells in adults

The intestinal epithelial lining plays a central role in the digestion and absorption of nutrients,but exists in a harsh luminal environment that necessitates continual renewal.This renewal process involves epithelial cell proliferation in the crypt base and later cell migration from the crypt base to the luminal surface.This process is dependent on multi-potent progenitor cells,or stem cells,located in each crypt.There are about 4 to 6 stem cells per crypt,and these stem cells are believed to generate distinct end-differentiated epithelial cell types,including absorptive cells,goblet cells,enteroendocrine cells and Paneth cells,while also maintaining their own progenitor cell state.Earlier studies suggested that intestinal stem cells were located either in the crypt base interspersed between the Paneth cells [i.e.crypt base columnar(CBC) cell model] or at an average position of 4 cells from the crypt base [i.e.label-retaining cells(LRC +4) model].Recent studies have employed biomarkers in the in vivo mammalian state to more precisely evaluate the location of these progenitor cells in the intestinal crypt.Most notable of these novel markers are Lgr5,a gene that encodes a G-protein-coupled receptor with expression restricted to CBC cells,and Bmi 1,which encodes a chromatin remodeling protein expressed by LRC.These studies raise the possibility that there may be separate stem cell lines or different states of stem cell activation involved in the renewal of normal mammalian intestinal tract.

Malignancy in adult celiac disease

Prior studies have suggested that the incidence of some neoplastic disorders,particularly malignant lymphoma and small intestinal adenocarcinoma,are increased in celiac disease.Earlier studies from the United Kingdom have also suggested a link between celiac disease and esophageal carcinoma,although this has not been confi rmed in North America.The risk of other gastrointestinal cancers seems to be limited.Gastric cancer does not appear to be detected more frequently,although direct endoscopic visualization of the upper gastrointestinal tract is now very common in patients with celiac disease.Colon cancer also appears to be limited in celiac disease,even in patients first diagnosed with celiac disease late in life.This has led to the hypothesis that untreated celiac disease may be protective,possibly owing to impaired absorption of fat or fat-soluble agents,including hydrocarbons and putative co-carcinogens implicated in the pathogenesis of colon cancer,which may be poorly absorbed and rapidly excreted.

Complications of collagenous colitis

Microscopic forms of colitis have been described, including collagenous colitis.This disorder generally has an apparently benign clinical course.However, a number of gastric and intestinal complications, possibly coincidental,may develop with collagenous colitis.Distinctive inflammatory disorders of the gastric mucosa have been described,including lymphocytic gastritis and collagenous gastritis.Celiac disease and collagenous sprue(or collagenous enteritis)may occur. Colonic ulceration has been associated with use of nonsteroidal anti-inflammatory drugs,while other forms of inflammatory bowel disease,including ulcerative colitis and Crohn's disease,may evolve from collagenous colitis.Submucosal"dissection",colonic fractures or mucosal tears and perforation from air insufflation during colonoscopy may occur and has been hypothesized to be due to compromise of the colonic wall from submucosal collagen deposition.Similar changes may result from increased intraluminal pressure during barium enema contrast studies.Finally,malignant disorders have also been reported,including carcinoma and lymphoproliferative disease.