Jacqueline L. Wolf

Risk of early surgery for Crohn's disease: implications for early treatment strategies.

OBJECTIVES:In this study we aimed to define the rate of early surgery for Crohns disease and to identify risk factors associated with early surgery as a basis for subsequent studies of early intervention in Crohns disease.METHODS:We assembled a retrospective cohort of patients with Crohns disease diagnosed between 1991 and 1997 and followed for at least 3 yr, who were identified in 16 community and referral-based practices in New England. Chart review was performed for each patient. Details of baseline demographic and disease features were recorded. Surgical history including date of surgery, indication, and procedure were also noted. Risk factors for early surgery (defined as major surgery for Crohns disease within 3 yr of diagnosis, exclusive of major surgery at time of diagnosis) were identified by univariate analysis. Multiple logistic regression was used to identify independent risk factors.RESULTS:Of 345 eligible patients, 69 (20.1%) required surgery within 3 yr of diagnosis, excluding the 14 patients (4.1%) who had major surgery at the time of diagnosis. Overall, the interval between diagnosis and surgery was short; one half of all patients who required surgery underwent operation within 6 months of diagnosis. Risk factors identified by univariate analysis as significantly associated with early surgery included the following: smoking; disease of small bowel without colonic involvement; nausea and vomiting or abdominal pain on presentation; neutrophil count; and steroid use in the first 6 months. Disease localized to the colon only, blood in the stool, use of 5-aminosalicylate, and lymphocyte count were inversely associated with risk of early surgery. Logistic regression confirmed independent associations with smoking as a positive risk factor and involvement of colon without small bowel as a negative risk factor for early surgery.CONCLUSIONS:The rate of surgery is high in the first 3 yr after diagnosis of Crohns disease, particularly in the first 6 months. These results suggest that improved risk stratification and potent therapies with rapid onset of action are needed to modify the natural history of Crohns disease.

Liver disease in pregnancy

The liver is one of the many organs affected by the physiologic and hormonal changes that occur during pregnancy. Hepatic disorders diagnosed before pregnancy may be unaffected or exacerbated by the pregnant state. Liver disorders that are specific to pregnancy, including hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, preeclampsia/ eclampsia, HELLP, and hepatic rupture, may have a profound impact on the morbidity and mortality rates of mother and fetus. Although an unequivocal diagnosis is often difficult to make, it should be attempted in a timely manner so that optimal treatment can be determined. After the diagnosis is made, maximizing the health of the mother and fetus determines future management.

Histologic Markers of Inflammation in Patients With Ulcerative Colitis in Clinical Remission

BACKGROUND & AIMS Mucosal healing, based on histologic analysis, is an end point of maintenance therapy for patients with ulcerative colitis (UC). There are few data on how histologic signs of inflammation correlate with endoscopic and peripheral blood measures of inflammation in these patients. We investigated patterns of histologic features of inflammation in patients with UC in clinical remission, and correlated these with endoscopic and biochemical measures of inflammation. METHODS We performed a prospective observational study of 103 patients with UC in clinical remission undergoing surveillance colonoscopy while receiving maintenance therapy with mesalamine or thiopurines; 2674 biopsy specimens were collected from 708 colonic segments. Each colonic segment was evaluated based on the Mayo endoscopic subscore and the Geboes histology score (range, 0-5.4). Biomarkers were measured in peripheral blood samples. RESULTS Histologic features of inflammation were found in 54% of patients receiving maintenance therapy; 37% had at least moderate inflammation based on histology scores. Of the 52 patients with endoscopic evidence only of left-sided colitis, 34% had histologic features of inflammation in their proximal colon. Histology scores correlated with endoscopic scores for per-segment inflammation (Spearman ρ = 0.65; P < .001). Patients with histology scores greater than 3.1 had a significantly higher mean level of C-reactive protein than those with scores less than 3.1. There were no differences among treatment groups in percentages of patients with histologic scores greater than 3.1. CONCLUSIONS Patients in clinical remission from UC still frequently have histologic features of inflammation, which correlate with endoscopic appearance. Patients with at least moderate levels of inflammation, based on histologic grading (score >3.1), have higher serum levels of C-reactive protein, which could be used as a surrogate marker of histologic inflammation.

The σ1 protein determines the extent of spread of reovirus from the gastrointestinal tract of mice

After intragastric inoculation of adult mice, type 1 reovirus was initially concentrated in Peyers patches over the first 4 hr after inoculation, then spread sequentially to the mesenteric lymph nodes and spleen. For type 3 reovirus, however, initial entry into Peyers patches in adult mice was followed by loss of viral infectivity so that by 4 hr after inoculation virtually no infectious virus was detected in the intestine, and spread to extraintestinal tissues did not occur. In 10-day-old mice, type 3 was capable of spread to the mesenteric lymph nodes but not the spleen. Thus, as animals aged there was a greater restriction of the spread of type 3 from the intestine. Studies using a field isolate of type 3 reovirus that is resistant to intestinal proteases, and genetic studies utilizing type 1 x type 3 viral reassortants, revealed that the viral sigma 1 protein determined the capacity of reovirus to spread from the intestine in both adult and 10-day-old mice. Thus, the interaction of reovirus with host defense mechanisms, and the age-dependent restriction of spread of type 3 reovirus from the intestine are mediated by the viral sigma 1 protein.

Determinants of colorectal cancer screening in women undergoing mammography

OBJECTIVES:Women who participate in screening for breast cancer are more likely to participate in screening for colorectal cancer. We studied such a motivated group of women to identify predictors of, and barriers to, participation in colorectal cancer screening by endoscopy.METHODS:We distributed surveys to 551 women ≥ 50 yr of age while they were awaiting mammography at four sites in and around Boston, MA from June to September, 2000. The 40-question survey assessed knowledge, attitudes, and beliefs about, and behaviors toward, breast and colorectal cancer screening. Regression models were used to determine factors associated with having had sigmoidoscopy or colonoscopy.RESULTS:Seventy-nine percent of the women completed all or part of the survey. Half (221/438) reported ever having had sigmoidoscopy or colonoscopy. Of these, 93% did so at the recommendation of their primary care provider. Factors associated with participation in endoscopic screening included compliance with annual fecal occult blood testing, a family history of colorectal cancer, and indifference toward the gender of the doctor performing the endoscopy.CONCLUSIONS:Women undergoing mammography overwhelmingly cite the recommendation of their primary care provider as the reason for participating in colorectal cancer screening by endoscopy. Women who preferred a female endoscopist were less likely to have been screened. Whenever possible, primary care providers should offer women the choice of a female endoscopist for colorectal cancer screening.

Cecal volvulus in pregnancy

Colonic volvulus is an important entity to consider in any pregnant patient with abdominal pain. X-ray and colonoscopy can be useful to obtain the earliest diagnosis, leading to surgical intervention if necessary. Limited use of x-rays with shielding of the fetus is of minimal risk and useful for early diagnosis of volvulus. Colonoscopy may confirm or exclude the diagnosis of colonic volvulus, detect mucosal ischemia, and avoid the requirement for emergency surgery by reducing the volvulus in cases in which ischemia is not present. If surgery is necessary for a cecal volvulus, cecostomy is a viable option because of a low rate of morbidity and subsequent volvulus recurrence.

Predictors of endoscopic inflammation in patients with ulcerative colitis in clinical remission.

Background:Patients with ulcerative colitis (UC) who are in clinical remission may still have underlying endoscopic inflammation, which is associated with inferior clinical outcomes. The goal of this study was to determine the prevalence of active endoscopic disease, and factors associated with it, in patients with UC who are in clinical remission. Methods:Prospective observational study in a single center. Patients with UC in clinical remission (by Simple Clinical Colitis Activity Index) were enrolled prospectively at the time of surveillance colonoscopy. Disease phenotype, endoscopic activity (Mayo subscore), and histologic score (Geboes) were recorded, and blood was drawn for peripheral blood biomarkers. Results:Overall, 149 patients in clinical remission were prospectively enrolled in this cohort; 81% had been in clinical remission for >6 months, and 86% were currently prescribed maintenance medications. At endoscopy, 45% of patients in clinical remission had any endoscopic inflammation (Mayo endoscopy subscore >0), and 13% had scores >1. In a multivariate model, variables independently associated with a Mayo endoscopic score >1 were remission for <6 months (P = 0.001), white blood count (P = 0.01), and C-reactive protein level (P = 0.009). A model combining these 3 variables had a sensitivity of 94% and a specificity of 73% for predicting moderate-to-severe endoscopic activity in patients in clinical remission (area under the curve, 0.86). In an unselected subgroup of patients who had peripheral blood mononuclear cell messenger RNA profiling, GATA3 messenger RNA levels were significantly higher in patients with endoscopic activity. Conclusions:Duration of clinical remission, white blood count, and C-reactive protein level can predict the probability of ongoing endoscopic activity, despite clinical remission in patients with UC. These parameters could be used to identify patients who require intensification of treatment to achieve mucosal healing.

Histology Grade Is Independently Associated With Relapse Risk in Patients With Ulcerative Colitis in Clinical Remission: A Prospective Study.

OBJECTIVES:Objective evidence of inflammation has been associated with the risk of relapse in patients with ulcerative colitis (UC) who are in clinical remission. We compared endoscopic and histologic grades for their ability to predict clinical relapse in this patient population.METHODS:Patients with UC in clinical remission were prospectively enrolled into an observational cohort. Baseline endoscopic scores (Mayo) and histological (Geboes) grades and blood markers were collected. All subjects were followed for 12 months and relapse determined using clinical indices.RESULTS:A total of 179 subjects were enrolled into the study and followed for 12 months. Clinical relapse occurred in 23%; 5% were hospitalized, and 2% underwent colectomy. In univariate analysis, the baseline Mayo endoscopy score and the Geboes histology grade were significantly associated with the later development of clinical relapse (P<0.001 for both), but only the histology grade remained significant in a multivariate model (P=0.006). The relative risk of clinical relapse was 3.5 (95% CI 1.9–6.4, P<0.0001) in subjects whose baseline Geboes grade was ≥3.1. The area under the curve was 0.73 for the Geboes histology grade to identify subjects at risk of future clinical relapse. Of the patients in clinical, endoscopic, and histological remission at baseline (n=82), only 7% had a clinical relapse over the subsequent 12 months.CONCLUSIONS:Histology grade has the strongest association with the risk of clinical relapse in patients with UC who are in clinical remission. Consideration should be given to including this end point in evaluating therapy for UC.

Adherence to and penetration of the intestinal epithelium by reovirus type 1 in neonatal mice

In 10-day-old suckling and adult mice, reovirus type 1 adheres selectively to and penetrates membranous epithelial (M) cells. To determine when M cells first appear, when they first transport reovirus, and if reovirus adheres to and is endocytosed by other epithelial cells in the first postnatal week, we examined neonatal mouse intestine by transmission electron microscopy after reovirus type 1 exposure. At 2 days M cells accounted for 0.9% of dome epithelial cells. By 9 days M cells had increased to 7.4%. Reovirus type 1 adherence to the surface of villus and dome epithelial cells showed marked variation in 2-6-day-old animals, but by 7 days only a few absorptive cell profiles had adherent reovirus. Adherence to greater than 50% of M-cell profiles occurred in all but 2 animals, but adherence to the majority of Peyers patch absorptive cell profiles was present only in some 4- and 5-day-old animals. Adherence to a majority of undifferentiated cell profiles occurred in some animals at all ages. Membranous epithelial cells endocytosed reovirus at all ages but only at 2 days did rare villus and dome absorptive cells endocytose reovirus into the apical cytoplasm. Thus, adherence of reovirus to the apical surface of mucosal epithelial cells is nonselective in newborn mice but becomes more selective within the first postnatal week with adherence by day 7 to most M-cell profiles, to a substantial but variable number of undifferentiated cell profiles, but to few absorptive cell profiles.

Therapy Insight: drugs for gastrointestinal disorders in pregnant women

The management and treatment of gastrointestinal ailments in pregnant women requires special attention and expertise, since the safety of the mother, fetus and neonate remains the primary focus. Nausea and vomiting during pregnancy is common, as is symptomatic gastroesophageal reflux disease. Peptic ulcer disease occurs less frequently and with fewer complications. Gastroenterologists and obstetricians should be familiar with safe treatment options for these conditions, because they can profoundly impair the quality of life of pregnant women. During pregnancy, constipation can develop de novo, or chronic constipation can increase in severity. Given the array of therapies for constipation, physicians must apprise themselves of drugs that are safe for both mother and fetus. Management of acute, self-limited diarrhea should focus on supportive therapy, dietary changes and maintenance of hydration. Treatment of chronic diarrhea should be considered in the context of therapy for the underlying disorder. Inflammatory bowel disease and irritable bowel syndrome present a unique therapeutic challenge—to control the disease while minimizing toxicity to the fetus and mother. Initiation and alteration of medical therapy for gastrointestinal disorders during pregnancy must be undertaken after discussion with the patients obstetrician.