Determination of Serum Antibodies to Clostridium difficile Toxin B in Patients with Inflammatory Bowel Disease

Clostridium difficile infection has increased in prevalence among patients with inflammatory bowel disease (IBD). Serum antibodies against C. difficile toxins have been detected in susceptible populations and may be protective; however, such antibodies have not been previously characterized in IBD patients. This study measured immunoglobulin G antibody levels to C. difficile toxin B in serum from IBD patients in remission and IBD patients in relapse. IBD patients demonstrated significantly higher antibody levels than non-IBD patients. In addition, a higher proportion of IBD patients in remission had positive antibody levels compared to IBD patients in relapse. Further characterization of antibody responses may elucidate understanding of susceptibility to C. difficile infection among IBD patients.

Adverse Metabolic Sequelae Following Restorative Proctocolectomy with an Ileal Pouch

Ileal pouch–anal anastomosis (IPAA) following total proctocolectomy has become the surgical treatment of choice for ulcerative colitis patients who have medically refractory disease or neoplasia. Unfortunately, various metabolic complications have been reported with this surgical procedure, including anemia, vitamin B12 deficiency, bile salt and fat malabsorption, vitamin D deficiency, bone loss, and nephrolithiasis. Recognition and early diagnosis of these complications are important when managing IPAA patients.

Cytomegalovirus Complicating Inflammatory Bowel Disease: A 10-YearExperience in a Community-Based, University-Affiliated Hospital

There is an ongoing debate regarding the significance of cytomegalovirus (CMV) in colonic biopsies and the effect of antiviral therapy in patients with inflammatory bowel disease (IBD). In order to evaluate the possible impact of CMV disease on IBD patients, we reviewed charts of patients admitted through the emergency department with diagnoses of IBD and CMV over a 10-year period (January 2000 to November 2009). Laboratory test results and pharmacology databases were scrutinized, and pathology slides were re-evaluated when possible. The control group consisted of a historical group of IBD patients with flares who had been similarly evaluated in the emergency department but who did not have a diagnosis of CMV. Both chi-square tests and the student’s t-test were used for analysis. The study consisted of 31 patients with IBD and CMV (median age, 60 years; 65% male; 58% ulcerative colitis patients). Immuno-histochemistry confirmed the diagnosis in 19 cases (61%). Nine patients with CMV and IBD underwent a colectomy (29%) compared to 65 of the 581 patients in the control group (11.2%), who were evaluated during the same time period but did not have CMV (P=.007). Mortality was similar in both groups. Of the patients with CMV, 11 received ganciclovir. No significant differences in outcomes were noted with antiviral therapy. Although CMV disease is relatively uncommon in IBD patients, its presence may designate an increased risk for colectomy for reasons that are not yet clear. Patient outcomes may be independently affected by age and comorbidities. Systematic prospective studies could help determine the true effects of CMV on IBD patients.

A Lesson in Basic Trial Statistics

While the number of clinical trials performed yearly is increasing, the application of these results to individual patients is quite difficult. This article reviews key portions of the process of applying research results to clinical practice. The first step involves defining the study population and determining whether these patients are similar to the patients seen in clinical practice in terms of demographics, disease type, and disease severity. The dropout rate should be compared between the different study arms. Design aspects, including randomization and blinding, should be checked for signs of bias. When comparing studies, clinicians should be aware that the outcomes being studied may vary greatly from one study to another, and some outcomes are much more reliable and valuable than others. The definition of clinical response should also be scrutinized, as it may be too lenient. Surrogate outcomes should be viewed cautiously, and their use should be well justified. Clinicians should also note that statistical significance, as defined by a P-value cutoff, may be the result of a large sample size rather than a clinically significant difference. The treatment effect can be estimated by calculating the number needed to treat, which will demonstrate whether changes in clinical practice are worthwhile. Finally, this article discusses some common issues that can arise with figures.

Acute Liver Failure in Adults: An Evidence-Based Management Protocol for Clinicians

With the goal of providing guidance on the provision of optimal intensive care to adult patients with acute liver failure (ALF), this paper defines ALF and describes a protocol for appropriately diagnosing this relatively rare clinical entity and ascertaining its etiology, where possible. This paper also identifies the few known therapies that may be effective for specific causes of ALF and provides a comprehensive approach for anticipating, identifying, and managing complications. Finally, one of the more important aspects of care for patients with ALF is the determination of prognosis and, specifically, the need for liver transplantation. Prognostic tools are provided to help guide the clinician in this critical decision process. Management of patients with ALF is complex and challenging, even in centers where staff members have high levels of expertise and substantial experience. This evidence-based protocol may, therefore, assist in the delivery of optimal care to this critically ill patient population and may substantially increase the likelihood of positive outcomes.

Psychosocial Factors Contributing to Inflammatory Bowel Disease Activity and Health-Related Quality of Life

Objective: This study aimed to examine the contributions of coping and social constraint to disease activity and health-related quality of life (HRQOL) and to examine group differences in disease activity and HRQOL between patients with high versus low anxiety or depression symptoms in adults with inflammatory bowel disease (IBD). Methods: This study was a retrospective analysis in which disease activity was measured with either the Harvey-Bradshaw Index or the Simple Clinical Colitis Activity Index. HRQOL was measured with the Short Inflammatory Bowel Disease Questionnaire. Coping was measured with a modified COPE questionnaire. Anxiety and depression symptoms were measured with the Hospital Anxiety and Depression Scale. Social constraint was measured with the Social Constraint Questionnaire. Correlational and regression analyses were performed to assess the relationships between social constraint, coping, anxiety symptoms, depression symptoms, and HRQOL and disease activity. Results: Data from 80 adults with IBD were reviewed. Social constraint, disengagement coping, anxiety symptoms, and depression symptoms were inversely correlated with HRQOL. Disengagement coping was positively correlated with disease activity. Regression analyses showed that smokers had significantly worse HRQOL than nonsmokers and that greater use of engagement coping was associated with significantly diminished HRQOL. Regression analyses also showed that patients diagnosed between 17 and 40 years of age were significantly less likely to have active disease than patients diagnosed before 16 years of age and that greater use of disengagement coping was associated with increased odds of having active disease. Conclusions: Medical providers should be aware that coexisting social constraint and symptoms of anxiety and depression are common in patients with IBD. Screening for these factors, as well as patients’ coping styles, should be strongly considered, and patients should be referred to mental health providers as appropriate.

Advances in the Treatment of Hepatitis C Virus Infection

Therapy for chronic hepatitis C virus (HCV) infection with pegylated interferon α and ribavirin leads to suboptimal rates of viral eradication in patients with genotype 1 HCV, the most common viral strain in the United States and many other countries. Recent advances in the study of viral kinetics, host factors that predict response to antiviral therapy, and viral protein structure have established the foundation of a new era in the treatment of HCV infection. The HCV NS3/4A protease inhibitors boceprevir and telaprevir, the first 2 agents in a new and promising generation of direct-acting antiviral agents to have completed phase III studies, were approved by the US Food and Drug Administration in May 2011. The addition of these HCV protease inhibitors to standard therapy has been demonstrated to dramatically improve sustained virologic response rates, both in treatment-naïve patients and in prior relapsers and nonresponders. These novel agents represent only the beginning of a revolution in HCV therapy, which will include additional protease inhibitors as well as other classes of drugs currently under investigation, such as polymerase inhibitors, NS5A inhibitors, and host factor inhibitors such as cyclophilin antagonists. The future of HCV therapy holds promise for significantly higher sustained virologic response rates with shorter treatment durations, as well as the intriguing potential to achieve virologic cure with interferon-free combination therapy regimens.

Mimicry and Deception in Inflammatory Bowel Disease and Intestinal Behçet Disease

Behçet disease (BD) is a rare, chronic, multisystemic, inflammatory disease characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. Intestinal BD occurs in 10–15% of BD patients and shares many clinical characteristics with inflammatory bowel disease (IBD), making differentiation of the 2 diseases very difficult and occasionally impossible. The diagnosis of intestinal BD is based on clinical findings—as there is no pathognomonic laboratory test—and should be considered in patients who present with abdominal pain, diarrhea, weight loss, and rectal bleeding and who are susceptible to intestinal BD. Treatment for intestinal BD is similar to that for IBD, but overall prognosis is worse for intestinal BD. Although intestinal BD is extremely rare in the United States, physicians will increasingly encounter these challenging patients in the future due to increased immigration rates of Asian and Mediterranean populations.

Intestinal Methane Production in Obese Individuals Is Associated with a Higher Body Mass Index

Background: Obesity is an epidemic that affects 1 in 3 individuals in the United States, and recent evidence suggests that enteric microbiota may play a significant role in the development of obesity. This study evaluated the association between methanogenic archaea and obesity in human subjects. Methods: Subjects with a body mass index (BMI) of 30 kg/m2 or higher were prospectively recruited from the weight loss program of a tertiary care medical center. Subjects who met the study’s inclusion criteria were asked to complete a questionnaire that included a series of visual analogue scores for bowel symptom severities. Subjects then provided a single end-expiratory breath sample to quantitate methane levels. Bivariate and multivariate analyses were used to determine associations with BMI. Results: A total of 58 patients qualified for enrollment. Twenty percent of patients (n=12) had breath test results that were positive for methane (>3 parts per million [ppm]), with a mean breath methane concentration of 12.2±3.1 ppm. BMI was significantly higher in methane-positive subjects (45.2±2.3 kg/m2) than in methane-negative subjects (38.5±0.8 kg/m2; P=.001). Methane-positive subjects also had a greater severity of constipation than methane-negative subjects (21.3±6.4 vs 9.5±2.4; P=.043). Multiple regression analysis illustrated a significant association between BMI and methane, constipation, and antidepressant use. However, methane remained an independent predictor of elevated BMI when controlling for antidepressant use (P<.001) and when controlling for both constipation and antidepressant use (6.55 kg/m2 greater BMI; P=.003). Conclusion: This is the first human study to demonstrate that a higher concentration of methane detected by breath testing is a predictor of significantly greater obesity in overweight subjects.

Mucosal Healing in Inflammatory Bowel Disease—A True Paradigm of Success?

Mucosal healing is gaining more acceptance as a measure of disease activity in Crohn’s disease and ulcerative colitis, and it is also gaining acceptance as an endpoint in clinical trials. Recent publications have correlated achievement of mucosal healing with good outcomes. Currently, there is no validated definition of what constitutes mucosal healing in inflammatory bowel disease. In clinical trials of ulcerative colitis, mucosal healing has been achieved with 5-aminosalicylates, corticosteroids, azathioprine, and infliximab. For Crohn’s disease, mucosal healing has been achieved with corticosteroids, infliximab, and adalimumab, and mucosal healing has been maintained with infliximab. Achievement of long-term mucosal healing has been associated with a decreased risk of colectomy and colorectal cancer in ulcerative colitis patients, a decreased need for corticosteroid treatment in Crohn’s disease patients, and a trend toward a decreased need for hospitalization in Crohn’s disease patients. Unfortunately, assessment of mucosal healing requires regular use of endoscopy, which is associated with increased costs, patient discomfort, and side effects. Biomarkers such as fecal calprotectin, fecal lactoferrin, serum C-reactive protein, and fecal S100A12 have been shown to correlate with disease activity in ulcerative colitis and Crohn’s disease; in the future, these biomarkers might be used as surrogate markers for mucosal healing. Newer clinical trials are incorporating mucosal healing as an endpoint for evaluation of efficacy. However, before mucosal healing will be sufficient to guide therapy, clinicians need a standard definition of mucosal healing and a consistently used, prospectively validated scale with good interobserver agreement.

A Technical Review and Clinical Assessment of the Wireless Motility Capsule

Abstract: The wireless motility/pH capsule (WMC) is an orally ingested, nondigestible, data recording device that enables the simultaneous assessment of regional and whole gut transit. Approved by the US Food and Drug Administration for the evaluation of patients with suspected delayed gastric emptying and the evaluation of colonic transit time in patients with chronic idiopathic constipation, this capsule continuously measures the temperature, pH, and pressure of its surrounding environment while traveling through the gastrointestinal tract (via gut peristalsis) until exiting the body through the anus. Validated patterns in pH and temperature recordings allow for accurate measurement of gastric emptying, small bowel transit, colonic transit, and whole gut transit times. The WMC is a nonradioactive, office-based, gastrointestinal transit testing modality shown in several clinical trials to be a suitable alternative to scintigraphy and radiopaque marker studies in measuring gastric emptying, small bowel, colonic, and whole gut transit times. Unlike widely available transit tests, which provide only region-specific transit data, the WMC offers the benefit of measuring gastric, small bowel, and colonic transit times in a single examination. The WMC also provides intraluminal pressure readings throughout the digestive tract, offering a noninvasive means by which to assess gastrointestinal motility. The WMC should be considered the transit study of choice for individuals suspected of having altered transit in more than one region of the gastrointestinal tract. This review summarizes the features and performance characteristics of the WMC as well as provides a summary on how this diagnostic modality is most effectively used in the assessment of gastrointestinal symptom complexes due to suspected abnormalities in transit.

The Value of Formal Clinical Research Training in Initiating a Career as a Clinical Investigator

Abstract: The aim of this study was to determine whether formal clinical research training is of value in the initiation of a successful career as a clinical investigator. We conducted a retrospective review of the career choices of all 25 fellows who entered the Academic Clinical Research Track at Brigham and Women’s Hospital since its inception in 1995 and examined the impact of formal clinical research training during their fellowship on their career choice. The primary measure of a successful career as a clinical investigator was the obtainment of external funding for clinical research within 3 years of completion of fellowship. Thirteen of the 25 fellows (52%) received a Master of Public Health (MPH) degree at the Harvard School of Public Health during their fellowship. Ten of these
13 fellows (77%) obtained external funding for clinical research within 3 years of completion of their fellowship. None of the
5 fellows who had already obtained an MPH degree prior to their fellowship and none of the 7 fellows who completed a 7-week summer Program in Clinical Effectiveness but did not complete an MPH degree attempted to receive external funding for clinical research within 3 years of completion of their fellowship. We conclude that formal clinical research training culminating in an MPH degree was extremely valuable in the initiation of a successful career as a clinical investigator.

Pathophysiology, Evaluation, and Treatment of Bloating: Hope, Hype, or Hot Air?

Abstract: Abdominal bloating is commonly reported by men and women of all ages. Bloating occurs in nearly all patients with irritable bowel syndrome, and it also occurs in patients with other functional and organic disorders. Bloating is frequently disturbing to patients and frustrating to clinicians, as effective treatments are limited and are not universally successful. Although the terms bloating and abdominal distention are often used interchangeably, these symptoms likely involve different pathophysiologic processes, both of which are still not completely understood. The goal of this paper is to review the pathophysiology, evaluation, and treatment of bloating and abdominal distention.

Current and Future Role of Serogenomics in Ulcerative Colitis

Abstract: Ulcerative colitis (UC), a chronic inflammatory bowel disease, occurs in genetically susceptible individuals who mount inappropriate immune responses to endoluminal antigens. Serologic and genetic markers have shown great potential for clinical application in Crohn’s disease (CD), particularly for prognostication. However, their use is not as well established in UC. The aim of this paper is to highlight the clinical relevance of these markers for diagnostics and prognostication in UC. This review identified studies that cited the use of serum and genetic biomarkers in UC when these biomarkers were used in diagnostic, prognostic, and therapeutic response prediction applications. Several serologic and genetic markers associated with UC were identified, and this review presents and summarizes these data, focusing on the biomarkers’ established and emerging diagnostic and prognostic utility. Although more established in CD, the data provided by serologic and genetic testing in UC has the potential to enhance clinical decision making.

The Current Economic Burden of Cirrhosis

Abstract: Cirrhosis is a worldwide problem that is associated with a substantial economic burden. Hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and alcoholic liver disease are the main causes of cirrhosis, but cost-effective preventive strategies are only available for HBV infection. Treatment algorithms for HBV infection and HCV infection are numerous and may be economically advantageous, depending on the regimen utilized; however, effective treatment for alcoholic liver disease is lacking, with abstinence from alcohol consumption continuing to be the main treatment strategy. In addition, liver transplantation (the only cure for cirrhosis) continues to consume substantial economic resources despite a recent reduction in overall cost. More sensitive predictors of post–liver transplantation disability could reduce this cost by allowing interventions that would promote productivity and increase health-related quality of life after liver transplantation. This paper highlights recent publications that evaluate the cost-effectiveness of strategies that prevent or treat the main causes of cirrhosis as well as publications that assess the impact of quality of life on the overall cost burden of the disease.

Predictors of Aggressive Inflammatory Bowel Disease

Abstract: Inflammatory bowel disease comprises a group of conditions characterized by idiopathic inflammation of the gastrointestinal tract. The natural course of disease can range from an indolent course with prolonged periods of remission to aggressive, incapacitating disease. Predicting which patients are more susceptible to developing severe disease is important, especially when choosing therapeutic agents and treatment strategies. This paper reviews current evidence on the main demographic, clinical, endoscopic, histologic, serologic, and genetic markers that predict aggressive inflammatory bowel disease. In ulcerative colitis, we considered disease to be aggressive when patients had a high relapse rate, need for admission and/or surgery, development of colon cancer, or extraintestinal manifestations. We defined aggressive Crohn’s disease as having a high relapse rate, development of penetrating disease, need for repeat surgery, or multiple admissions for flares. In Crohn’s disease, involvement of the upper gastrointestinal tract and ileum, penetrating disease, early age at diagnosis, smoking, extensive ulceration of the mucosa, high titers of serum antibodies, and mutations of the NOD2 gene are markers of aggressive disease. In ulcerative colitis, patients with more extensive involvement of the colon (pancolitis) have more symptomatology and are at higher risk for needing a colectomy and developing colon cancer. Also, plasmocytic infiltration of the colonic mucosa and crypt atrophy predict treatment failure. As with diagnosis, no single method can predict disease aggressiveness. Multiple serologic and genetic tests are being developed to refine the accuracy of prediction. Endoscopic findings can also predict the future course of disease. At present, clinical manifestations are the most useful way to make therapeutic decisions.

Managing Pain in Inflammatory Bowel Disease

Abstract: Pain is a common complaint in inflammatory bowel disease, and it has significant consequences for patients’ quality of life. A thorough evaluation to determine the source of patients’ pain should include clinical, laboratory, radiologic, and endoscopic assessments as indicated. Differentiating among active inflammation, secondary complications, and functional pain can be complicated. Even when all active disease is adequately treated, clinicians are often left with the difficulty of managing chronic pain. This paper will review the benefits and limitations of several commonly used treatments and promising future therapies. A suggested treatment algorithm will provide some guidance in this challenging area of inflammatory bowel disease management.

Defining Readmission Risk Factors for Liver Transplantation Recipients

Abstract: Liver transplantation (LT) is a costly but effective treatment for end-stage liver disease (ESLD). However, there are minimal data on the patterns of and risk factors for hospital readmission after LT. The aim of this study was to determine the frequency of and risk factors for rehospitalization after LT. Consecutive adult patients who underwent LT at a single center (n=208) were prospectively studied over a 30-month period. Within 90 days of LT, 30.3% of LT recipients were readmitted to the hospital. Recipient and donor age, Model for End-Stage Liver Disease score, cold ischemia time, type of hepatic graft, length of hospitalization after LT, and occurrence of operative/postoperative complications had no association with the risk for readmission (P>.05). The length of stay in intensive care was negatively correlated with readmission (hazard ratio, 0.92; P=.028). ESLD from hepatitis C virus (HCV) infection as an indication for LT was the only factor associated with an increased risk for readmission (hazard ratio, 1.91; P=.010). Further studies are needed to explore the reasons for readmission among LT recipients, particularly those with HCV infection, in order to devise cost-savings policies for post-LT care.

Immune Tolerant Hepatitis B: A Clinical Dilemma

Abstract: Chronic hepatitis B virus infection remains a global health concern, with perinatal transmission still a problem in many countries. Several new therapies for chronic hepatitis B virus infection have recently been introduced that can safely and effectively suppress viral replication with a low risk of resistance; thus, it has become increasingly tempting for many clinicians to treat patients in the immune tolerant stage of infection who have high levels of viremia yet persistently normal levels of transaminases. However, understanding the natural history of hepatitis B virus infection and how it pertains to disease progression, as well as how current therapies alter or do not alter this natural history, is important when deciding whether to treat these patients. This article will review the definition and natural history of immune tolerance, the current world guidelines and recommendations for treatment of immune tolerant patients, and data on the effectiveness of current therapies in this patient population.

Prognostic Value of Liver Fibrosis Biomarkers: A Meta-Analysis

Abstract: Aims and Methods: Several serum biomarkers such as FibroTest, aspartate transaminase–platelet ratio index (APRI), FIB-4, and liver stiffness measurement by FibroScan have been validated as alternatives to biopsy for the diagnosis of fibrosis in patients with chronic liver disease. This paper aims to assess the 5-year prognostic values of these biomarkers. A meta-analysis combined all published prognostic studies. Baseline biopsy and APRI data were used as references. Results: Only 3 biomarkers had several prognostic validations: FibroTest (4 studies; 2,396 patients), APRI (5 studies; 2,422 patients), and FIB-4 (3 studies; 1,184 patients). For the prediction of survival without liver-related death, the areas under the receiver operating characteristic curves (AUROCs) were 0.86 for biopsy (95% confidence interval [CI], 0.77–0.95), 0.88 for FibroTest (95% CI, 0.79–0.98), 0.73 for FIB-4 (95% CI, 0.62–0.85), and 0.66 for APRI (95% CI, 0.57–0.75). APRI had a significantly lower prognostic value versus biopsy, with a mean difference between AUROCs of –0.21 (95% CI, –0.33 to –0.10; P<.001); FIB-4 had a significantly lower prognostic value versus biopsy, with a mean difference between AUROCs of –0.21 (95% CI, –0.20 to –0.02; P=.02). Only FibroTest did not show a significant difference in prognostic value versus biopsy, with a mean difference in AUROCs of +0.02 (95% CI, –0.05 to +0.09; P=.85). Conclusion: FibroTest is a validated biomarker for the prognosis of patients with chronic liver disease.