Jeffrey B. Raskin

Diverticular disease of the colon

Summary Colonic diverticulosis refers to small outpouchings from the colonic lumen due to mucosal herniation through the colonic wall at sites of vascular perforation. Abnormal colonic motility and inadequate intake of dietary fibre have been implicated in its pathogenesis. This acquired abnormality is typically found in developed countries, and its prevalence rises with age. Most patients affected will remain entirely asymptomatic; however, 10–20% of those affected can manifest clinical syndromes, mainly diverticulitis and diverticular haemorrhage. As our elderly population grows, we can anticipate a concomitant rise in the number of patients with diverticular disease. Here, we review the incidence, pathophysiology, clinical presentation, and management of diverticular disease of the colon and its complications.

Diagnosis and management of diverticular disease of the colon in adults

PREAMBLE Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When data are not available, which will withstand objective scrutiny, a recommendation may be made based on a consensus of experts. Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty. Guidelines are intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. Given the wide range of choices in any health care problem, the physician should select the course best suited to the individual patient and the clinical situation presented. These guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. These guidelines are also approved by the governing boards of the American Gastroenterological Association and the American Society for Gastrointestinal Endoscopy. Expert opinion is solicited from the outset for the document. Guidelines are reviewed in depth by the committee, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time. The following guidelines are intended for adults and not for pediatric patients.

Diverticular disease of the colon.

Diverticular disease of the colon is quite common in developed countries, and its prevalence increases with age. Although present in perhaps two thirds of the elderly population, the large majority of patients will remain entirely asymptomatic. Nonetheless, an estimated 20% of those affected may manifest clinical illness, mainly diverticulitis, with its potential complications of abscesses, fistulas, and obstruction, as well as lower intestinal hemorrhage. The purpose of this report is to review our understanding of the epidemiology, pathophysiology, clinical presentation, and treatment options for this disorder.

Misoprostol Dosage in the Prevention of Nonsteroidal Anti-inflammatory Drug-Induced Gastric and Duodenal Ulcers: A Comparison of Three Regimens

Worldwide, nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed more frequently than any other group of medications [1]. Unfortunately, NSAID use is almost invariably accompanied by some degree of injury to the gastroduodenal mucosa, manifested by fecal blood loss or discovered by upper gastrointestinal endoscopy [2-10]. Gastroduodenal mucosal damage induced by NSAIDs may lead to the development of gastric or duodenal ulcers, or both, with the attendant possibility of hemorrhage and perforation in some patients. Several studies [4, 5, 8, 11-16] have shown that misoprostol, a synthetic analog of prostaglandin E1, affords significant protection against NSAID-induced gastric and duodenal ulcers; the drug has also been shown to reduce the incidence of ulcer complications [17]. However, the use of misoprostol at the currently recommended dosage of 200 g four times daily is associated with frequent side effects, which primarily affect the gastrointestinal tract. These side effects are generally mild but may lead to poor patient compliance. A lower dosage of misoprostol, such as 200 g twice or three times daily, might result in a lower incidence of adverse events (and, hence, better compliance) without adversely affecting efficacy. We sought to determine the effectiveness and tolerability of three different misoprostol regimens. Methods The study was a 12-week, randomized, parallel, placebo-controlled, double-blind comparison of three regimens of misoprostol (Cytotec, G.D. Searle & Co., Chicago, Illinois) and was done at 135 centers. A single study protocol was approved by the institutional review boards for all study sites. Informed consent was obtained from all patients. Patients qualifying for study entry had a clinical diagnosis of osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or the Reiter syndrome and were receiving NSAID therapy that was expected to continue uninterrupted for at least 3 additional months at a fixed dose. The following minimum daily NSAID dosages were required: ibuprofen, 1200 mg; piroxicam, 20 mg; naproxen, 750 mg; sulindac, 200 mg; tolmetin, 1200 mg; indomethacin, 75 mg; flurbiprofen, 200 mg; ketoprofen, 150 mg; or diclofenac, 150 mg. Qualifying patients had to be having upper gastrointestinal symptoms, such as pain, cramps, bloating, or heartburn. Before study entry, patients supplied a medical history and had a physical examination, upper gastrointestinal symptom assessment, routine laboratory tests, and upper gastrointestinal endoscopy. Patients with a gastric or duodenal mucosal defect 0.3 cm or less in diameter, a mucosal defect of any size with perceptible depth, or any esophageal erosions or ulcers were excluded from the study. Also excluded were patients who had had upper gastrointestinal surgery within 30 days of anticipated entry into the study and patients with upper gastrointestinal malignancy, pyloric obstruction, acute hepatitis, pancreatitis, inflammatory bowel disease, or a bleeding diathesis. Patients were assigned to their regimens according to a centralized, computer-generated randomization schedule. Each center was assigned with one or more randomization blocks of seven in sealed envelopes. Patients were assigned sequentially to receive one of four regimens: placebo four times daily; 200 g of misoprostol twice daily plus placebo twice daily; 200 g of misoprostol three times daily plus placebo once daily; or 200 g of misoprostol four times daily. One patient was assigned to the group receiving misoprostol four times daily for every two patients assigned to the other groups. These assignment ratios were chosen in light of the known therapeutic effectiveness of four-times-daily dosing. They were calculated to demonstrate a reduction in the rate of gastric ulcer development from 13% in the placebo group to 4% in each of the active treatment arms (twice daily, three times daily, and four times daily), and to show a similar reduction in duodenal ulcer development from 6.3% to 1%, with an overall error rate of 0.05% and a power of 80%. Blister cards of scored tablets were supplied by the sponsor and contained tablets of misoprostol, 200 g, or identical tablets composed of inert excipient. Labels on the blister packs indicated the breakfast, lunch, dinner, and bedtime doses. For the first 3 days of the study, patients were instructed to take one half of one tablet four times daily and to discard the other halves of the tablets. Subsequently, full tablets were taken. Patients who missed a dose were instructed to skip that dose. Each patient was provided with antacid tablets, 84 600 mg aluminum hydroxide (Amphogel, Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania), and instructed to take as many as four tablets per day as required for relief of upper abdominal symptoms during the first 3 weeks of the study. Study medication dispensed at one visit was collected and inventoried at the next visit to ensure at least 60% compliance in the dosing of misoprostol. Patients had endoscopic and upper gastrointestinal symptom evaluations after 4, 8, and 12 weeks of therapy. Endoscopic examinations included assessment of the gastric and duodenal mucosa. Patient Groups Analyzed Of the 1623 patients enrolled in the study, 1259 finished the trial. Of these, 1197 met major accession, study drug compliance, and endoscopic evaluation criteria and composed the evaluable group of patients. Primary analyses were done on this evaluable group. Confirmatory analyses were also done on the intention-to-treat group, which comprised patients who had received at least one dose of study medication. End Points A patient who developed an endoscopically confirmed gastric or duodenal ulcer ( 0.3 cm in diameter and with perceptible depth) during the study was considered a prophylaxis failure. Statistical Analysis The baseline demographic characteristics of the study treatment groups were compared using either the Pearson chi-square test (sex and race) or the Kruskal-Wallis test (age). To evaluate the efficacy of misoprostol therapy in the prevention of NSAID-induced gastric and duodenal ulcers, the following three pairwise comparisons were made: misoprostol twice daily compared with placebo, misoprostol three times daily compared with placebo, and misoprostol four times daily compared with placebo. In addition, comparisons of the incidence of NSAID-induced ulcers in the groups receiving misoprostol twice and three times daily with that in the group receiving misoprostol four times daily were done to determine evidence of similar effectiveness in the prevention of ulcers. Treatment-by-investigator interactions were assessed qualitatively. The dosage-response effect of misoprostol was determined by using a logistic regression analysis with ulcer occurrence as the dependent variable and dosage as the independent variable. The placebo group was not included for these analyses. Incidence rates for adverse events were calculated for body system, type of event, severity (mild, moderate, and severe), and relation to study drug (none, uncertain, and probable). Interregimen incidence rate comparisons were made using the unadjusted, two-tailed chi-square test. If chi-square assessment of incidence rates for the four regimens for an individual adverse event showed a statistically significant difference, incidence rates for the particular adverse event were further tested without the placebo group to distinguish differences among the three active treatment groups. Adverse events causing withdrawal from the study were compared across treatment groups using the Pearson chi-square test or the Fisher exact test. Dosage-response effect on adverse events was determined by using a logistic regression analysis with adverse event as the dependent variable and dosage as the independent variable. The statistical analysis was done by G.D. Searle & Co. Results Study Population The disposition and randomization of patients entered into the study (n = 1623) is presented in Table 1. Five patients received no medication and were excluded from the intention-to-treat group. A total of 421 patients was excluded from the intention-to-treat group (359 were withdrawn before reaching an end point and 62 were excluded for other reasons), leaving 1197 patients in the evaluable group. Table 1. Disposition of Patients Entered into the Study Demographic Characteristics Demographic data for the intention-to-treat group are shown in Table 2. Neither the intention-to-treat group nor the evaluable groups differed significantly with respect to age, sex, race, NSAID use, type of arthritis, prevalence of smoking, or alcohol use. Table 2. Demographic Characteristics of the Intention-to-Treat Group Gastric Ulcers Gastric ulcers (evaluable for the gastric ulcer group) were noted in 51 of 325 patients (15.7%) receiving placebo, in 29 of 358 patients (8.1%) receiving misoprostol twice daily, in 13 of 336 patients (3.9%) receiving misoprostol three times daily, and in 6 of 152 patients (4.0%) receiving misoprostol four times daily (Table 3). The incidence of gastric ulcers was significantly lower in groups receiving misoprostol twice daily (difference, 7.6% [95% CI, 2.7% to 12.5%]; P = 0.002), three times daily (difference, 11.8% [CI, 7.4% to 16.3%]; P < 0.001), and four times daily (difference, 11.7% [CI, 6.7% to 16.8%]; P < 0.001) than in the group receiving placebo. Pairwise comparison showed no statistical difference between the group receiving misoprostol four times daily and the groups receiving it three times or twice daily. However, a significant difference (difference, 4.2% [CI, 0.7% to 7.7%]; P = 0.02) was noted between the group receiving misoprostol twice daily and the group receiving it three times daily. A significant dose-response effect across treatment groups was noted (P = 0.02). Table 3. Pairwise Comparison of Rates of Gastric Ulcer in the Evaluable-for-Gastric-Ulcer Group Duodenal Ulcers Duodenal ulcer

Mesalamine Did Not Prevent Recurrent Diverticulitis in Phase 3 Controlled Trials

BACKGROUND & AIMS No therapy has been proven to prevent the recurrence of diverticulitis. Mesalamine has shown efficacy in preventing relapse in inflammatory bowel disease, and there is preliminary evidence that it might be effective for diverticular disease. We investigated the efficacy of mesalamine in preventing recurrence of diverticulitis in 2 identical but separate phase 3, randomized, double-blind, placebo-controlled, multicenter trials (identical confirmatory trials were conducted for regulatory reasons). METHODS We evaluated the efficacy and safety of multimatrix mesalamine vs placebo in the prevention of recurrent diverticulitis in 590 (PREVENT1) and 592 (PREVENT2) adult patients with ≥1 episodes of acute diverticulitis in the previous 24 months that resolved without surgery. Patients received mesalamine (1.2 g, 2.4 g, or 4.8 g) or placebo once daily for 104 weeks. The primary end point was the proportion of recurrence-free patients at week 104. Diverticulitis recurrence was defined as surgical intervention at any time for diverticular disease or presence of computed tomography scan results demonstrating bowel wall thickening (>5 mm) and/or fat stranding consistent with diverticulitis. For a portion of the study, recurrence also required the presence of abdominal pain and an increase in white blood cells. RESULTS Mesalamine did not reduce the rate of diverticulitis recurrence at week 104. Among patients in PREVENT1, 53%-63% did not have disease recurrence, compared with 65% of those given placebo. Among patients in PREVENT2, 59%-69% of patients did not have disease recurrence, compared with 68% of those given placebo. Mesalamine did not reduce time to recurrence, and the proportions of patients requiring surgery were comparable among treatment groups. No new adverse events were identified with mesalamine administration. CONCLUSIONS Mesalamine was not superior to placebo in preventing recurrent diverticulitis. Mesalamine is not recommended for this indication. ClinicalTrials.gov ID: NCT00545740 and NCT00545103.

Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study.

Background Occult celiac disease has been reported in 0 to 6% of adults presenting with iron-deficiency anemia. Most prior studies have been retrospective or screened only a selected population of patients with small bowel biopsies. To more accurately define the true prevalence of this disorder in patients presenting with iron-deficiency anemia (with or without stool hemoccult positivity), we initiated this prospective study. Methods Esophagogastroduodenoscopy with small bowel biopsies and colonoscopy were performed in all iron-deficiency anemia patients (including those with hemoccult-positive stools) referred to the gastroenterology service during a 2-year period (1998–2000). Inclusion criteria included iron-deficiency anemia as defined by a serum ferritin <25 ng/ml and anemia with hemoglobin <12 g/dl. Patients were excluded for documented prior erosive, ulcerative, or malignant disease of the gastrointestinal tract, previous gastrointestinal surgery, overt gastrointestinal bleeding within the past 3 months, or inability to access the duodenum for biopsy. All patients underwent upper endoscopy with more than two biopsies of the distal duodenum and colonoscopy. A serum immunoglobulin A antiendomysial antibody test was to be performed in those patients with a positive small bowel biopsy to confirm the diagnosis of celiac disease. Results One hundred five of 139 consecutive patients with iron-deficiency anemia met the inclusion criteria and were enrolled in the study. Fifty-seven men (mean age, 51.6 yr) and 48 women (mean age, 54.1 yr) constituted the study population. The demographics of this study population included 36 blacks, 38 Hispanics, and 22 whites. Nine patients were of mixed or unknown ethnic background. Forty-three and eight-tenths percent of the men and 37.5% of women had hemoccult-positive stools, accounting for a total of 40.9% of the study patients. Upper endoscopic findings included gastritis in 22.8%, gastric ulcers in 9.5%, duodenitis in 8.5%, esophagitis in 7.6%, Barrett’s ulcer in 2.8%, duodenal ulcer in 2.8%, gastric polyp in 2.8%, and celiac disease in 2.8%. Colonoscopic findings included colon polyps in 21.9%, diverticula in 10.4%, and hemorrhoids in 16.1%. Multiple findings were found in 32.3% of patients, and there were no findings in 28.5% of patients. Conclusion The prevalence of occult celiac disease in this prospective study of patients presenting with iron-deficiency anemia was 2.8%. A significant number of other gastrointestinal lesions amenable to therapy were also found on upper and lower endoscopy in these patients. Given the treatable nature of celiac disease, it should be screened for in patients with unexplained iron-deficiency anemia with or without hemoccult-positive stools.

The uncleared fundal pool in acute upper gastrointestinal bleeding: implications and outcomes

BACKGROUND The implications and outcomes of patients with an uncleared fundal pool of blood found at emergent upper endoscopy are not well described. METHODS We reviewed the records of 484 consecutive patients who presented over a 12-month period to our medical center with acute upper gastrointestinal hemorrhage. All patients underwent upper endoscopy within 24 hours of their initial presentation. Patients with an uncleared fundal pool of blood at initial endoscopy were included in this study, and their findings and outcomes were compared with a randomly selected subgroup of these same patients who did not have residual gastric blood. RESULTS Sixty-one patients (13%) had uncleared fundal pools despite gastric lavage and patient positioning. Findings on initial endoscopy included esophageal varices in 29 (47%), gastric ulcer in 12 (20%), portal hypertensive gastropathy in 5 (8%), Mallory-Weiss tear in 5 (8%), duodenal ulcer in 5 (8%), gastric varices in 4 (7%), Dieulafoys lesion in 2 (3%), and other in 7 (11%). Twelve of these 61 patients had multiple findings and 4 (7%) had no lesion identified. Thirty-two of the 61 patients (52%) had at least one follow-up endoscopy, with new fundal lesions identified in 13 (41%): portal hypertensive gastropathy in 8, gastric ulcer in 2, gastric varices in 2, and leiomyoma in 1. Of these 13 new findings, 5 (38%) were judged significant either by the presence of active bleeding or stigmata of recent hemorrhage. Of the 4 patients with no identifiable lesion on initial endoscopy, 3 had a follow-up endoscopy and 2 were found to have a significant new finding in the fundus. The control group had a statistically significant lower percentage of endoscopic findings related to portal hypertension. Recurrent bleeding during the index hospitalization occurred in 54% of the patients with uncleared fundal pools versus 11% of the control group (0 < 0.01). Length of stay, number of units of blood transfused, need for emergent surgery for bleeding, as well as overall and bleeding-related mortality were all significantly greater in the patients with the uncleared fundal pool than in the control patients. CONCLUSIONS The inability to clear a fundal pool of blood at emergent upper endoscopy is associated with significant morbidity and mortality. Further, new fundal lesions can be identified in 41% of patients on follow-up examination, with many being clinically significant. These data support the importance of clearing a fundal pool in patients undergoing endoscopy for upper gastrointestinal bleeding.

History, incidence, and epidemiology of diverticulosis.

Diverticulosis of the colon is a very common condition. Described as early as the 17th century, most of the information we now have is based on much of the work during the 20th century. Age, sex, race, and geography all play a specific role in the development of diverticula. It is the merging of these factors that changes the prevalence of diverticula and their manifestations. Symptomatic diverticula can lead to serious complications requiring both medical and surgical interventions to treat these complications when they occur. This review will focus on the history and epidemiology of diverticulosis in regard to age, sex, race, geography, and the epidemiology of complicated diverticular disease.

Transendoscopic electrosurgical incision of lower esophageal (Schatzki) rings: a new treatment modality

The lower esophageal ring (Schatzki ring) is a diaphragm-like narrowing not infrequently found in the lower esophagus, usually associated with a sliding hiatal hernia. These rings consist of submucosal fibrosis with normal overlying musoca and occur at the junction of the squamous epithelium of the esophagus and the columnar epithelium of the stomach. Although most patients are asymptomatic, the ring may be responsible for dysphagia and, in particular, cause intermittent food impaction. A variety of therapeutic options are available, but none are consistently effective in relieving symptoms.• Transendoscopic electrosurgical incision, a new approach to the treatment of lower esophageal rings in which conventional bougienage could not be accomplished or failed, is described in this report.

Acquired hyperplastic gastric polyps in solid organ transplant patients

Abstract OBJECTIVE: We report a series of patients who developed hyperplastic gastric polyps after solid organ transplantation. METHODS: A retrospective review of patients with solid organ transplantation from January 1997 to December 1999 was performed. Patients with gastric polyps found during endoscopy were included. Demographic data, polyp characteristics (endoscopic and histological), time of endoscopy, and treatment regimens were analyzed. RESULTS: A total of 10 (seven men, three women) transplanted patients (six cardiac, three liver, and one kidney) with gastric polyps were identified. The median age was 61 yr (27–71 yr), and median time of endoscopy after transplantation was 11 months (3–28 months). Eight patients had endoscopy before or soon after transplantation, with no evidence of polyps. Nine patients had multiple polyps (three or more), and one had a single pedunculated polyp. Polyps were confined to the antrum in eight patients, antrum and body in one patient, and fundus in one patient. All polyps biopsied were found to be hyperplastic and without adenomatous or malignant changes. Cytomegalovirus serology was negative in nine patients. Each patient received standard immunosuppression that included a calcineurin inhibitor and steroids. Steroids were tapered and stopped by 3 months. Azathioprine was added in five patients and mycophenolate mofetil in one patient. CONCLUSIONS: The development of gastric polyps after organ transplantation has not been previously reported. The development of these gastric polyps (hyperplastic and multiple) is concerning as a malignant potential has been recognized in patients harboring multiple hyperplastic gastric polyps. The exact cause of these polyps is unknown. The association with immunosuppressive therapy as well as the natural history of these acquired hyperplastic gastric polyps needs further investigation.