OBJECTIVES:

Very little is known about whether the reported health-related impact of constipation is worse in people who experience constipation over a long period of time vs. those with more transient symptoms. We aimed to determine the impact of persistent vs. transient constipation on health-related quality of life (QOL), depression, and mortality.

METHODS:

We analyzed data from 5,107 women (aged 70-75 years in 1996) who answered "Have you had constipation in the past 12 months?" in all five surveys sent out every 3 years of the Australian Longitudinal Study on Women's Health.

RESULTS:

Of the 5,107 women, 20.9, 54.1, and 24.7% reported having persistent constipation on at least 4 out of 5 surveys, transient constipation reported on 1-3 surveys, or none reported over the 15-year time frame, respectively. Women who reported persistent constipation had significantly lower scores for all domains of QOL on the SF-36 except role-emotional, and had higher levels of self-reported depression, even after adjusting for number of chronic illnesses and fluid intake. Mortality rates were increased when comparing women with no reported constipation with persistently reported constipation (8.2% vs. 11%, odds ratio = 1.32, 95% confidence interval 1.0, 1.74, P = 0.05) controlling for specific chronic illnesses.

CONCLUSIONS:

Persistent constipation among older women is associated with poor health outcomes.Am J Gastroenterol advance online publication, 14 May 2013; doi:10.1038/ajg.2013.137.

OBJECTIVES:

Colorectal cancer (CRC) screening is underutilized. To effect change, we must understand reasons for underuse at multiple levels of the health-care system. We evaluated patient, provider, and clinic factors that predict variation in CRC screening among primary-care clinics and primary-care providers (PCPs).

METHODS:

We analyzed electronic medical record (EMR) data for 34,319 adults eligible for CRC screening, 19 clinics, and 97 PCPs in a large, academic physician group. Detailed data on potential patient, provider, and clinic predictors of CRC screening were obtained from the EMR. PCP perceptions of CRC screening barriers were measured via survey. The outcome was completion of CRC screening at the patient level. Multivariate logistic regression with clustering on clinics obtained adjusted odds ratios and 95% confidence intervals for potential predictors of CRC screening at each level.

RESULTS:

Seventy-one percentage of patients completed CRC screening. Variation in screening rates was seen among clinics (51-80%) and among PCPs (51-82%). Significant predictors of completing CRC screening were identified at all levels: patient (older age, white race, being married, primarily English-speaking, having commercial insurance plans vs. Medicare or Medicaid, and higher health-care resource utilization), provider (larger panel size of patients eligible for CRC screening), and clinic (hospital-owned, shorter distance to nearest optical colonoscopy center).

CONCLUSIONS:

Variation in CRC screening exists among primary-care clinics and providers within a single clinic. Predictors of variation can be identified at patient, provider, and clinic levels. Quality improvement interventions addressing CRC screening need to be directed at multiple levels of the health-care system.Am J Gastroenterol advance online publication, 14 May 2013; doi:10.1038/ajg.2013.127.

OBJECTIVES:

Fecal calprotectin (FC) is increasingly used during the diagnosis of inflammatory bowel disease (IBD), outperforming blood markers during investigation in children. Tests that reduce endoscopy rates in children with suspected gut inflammation would be beneficial. We aimed to determine the usefulness of FC in children undergoing their primary investigation for suspected IBD by systematic review and meta-analysis.

METHODS:

An electronic search was performed with keywords relating to IBD and calprotectin in multiple electronic resources from 1946 to May 2012; a hand search was also performed. Inclusion criteria were studies that reported FC levels before the endoscopic investigation of IBD in patients less than 18 years old. Studies were evaluated using the Quality Assessment of Diagnostic Accuracy Studies tool, and a meta-analysis was performed using a hierarchical summary receiver operating curve model.

RESULTS:

Eight papers met the inclusion criteria (six prospective and two retrospective case-control studies); methodological quality was determined in detail for each study. The 8 studies presented FC levels at presentation in 715 patients, 394 pediatric IBD patients, and 321 non-IBD controls. Pooled sensitivity and specificity for the diagnostic utility of FC during the investigation of suspected pediatric IBD were 0.978 (95% confidence interval (CI), 0.947-0.996) and 0.682 (95% CI, 0.502-0.863), respectively; the positive and negative likelihood ratios were 3.07 and 0.03, respectively.

CONCLUSIONS:

FC has a high sensitivity and a modest specificity during the diagnosis of suspected pediatric IBD. Further work is required to determine the effect of FC levels on endoscopy rates and its role during the re-evaluation of those with confirmed disease.Am J Gastroenterol advance online publication, 14 May 2013; doi:10.1038/ajg.2013.131.

OBJECTIVES:

Rituximab, an anti-CD20 monoclonal antibody that selectively depletes B cells, has shown promise in autoantibody-associated, immune-mediated disorders. As ursodeoxycholic acid (UDCA) is not successful in all patients with primary biliary cirrhosis (PBC), additional treatment options are necessary. The objective of this study was to assess the safety and efficacy of rituximab in patients with PBC refractory to UDCA.

METHODS:

Fourteen PBC patients refractory to UDCA received two rituximab infusions (1,000 mg) 2 weeks apart. The primary efficacy outcome was normalization and/or 25% improvement in serum alkaline phosphatase (ALP) concentration at 6 months.

RESULTS:

The median age was 53 years, and 92% were female and antimitochondrial antibody (AMA) positive. The median UDCA dosage was 15.3 mg/kg/day (interquartile range 14.5-17.8). Although rituximab was well tolerated, one patient withdrew due to an asthma exacerbation during the first infusion. Effective B-cell depletion was observed in the remaining 13 patients, including three that developed human anti-chimeric antibodies. ALP normalization and/or ≥25% improvement was observed in three patients (23%) at 6, 12, and 18 months. Significant reductions in median ALP (from 259 U/l at baseline to 213 U/l at 6 months; median decrease 16%), and serum IgM and AMA levels were observed at 6 months. Although fatigue was stable, pruritus improved in 60% of patients at 12 months (vs. 8% with worsening pruritus).

CONCLUSIONS:

Selective B-cell depletion with rituximab was safe and associated with a significant decrease in autoantibody production, but had limited biochemical efficacy in PBC patients with an incomplete response to UDCA.Am J Gastroenterol advance online publication, 7 May 2013; doi:10.1038/ajg.2013.51.

OBJECTIVES:

Several anti-tumor necrosis factor-α (TNFα) antibodies have demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC). These drugs carry the theoretical risk of opportunistic infection, but no systematic review and meta-analysis has examined this issue specifically.

METHODS:

MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through to November 2012). Randomized controlled trials (RCTs) recruiting adults with active or quiescent CD or UC comparing anti-TNFα therapy with placebo were eligible. Dichotomous data were pooled to obtain a relative risk (RR) of opportunistic infection, with a 95% confidence interval (CI). The number needed to harm (NNH) was estimated from the reciprocal of the risk difference from the meta-analysis.

RESULTS:

The search strategy identified 20,563 citations, 21 of which were eligible, reporting 22 separate RCTs with between 2 and 56 weeks of follow-up. In total, there were 39 (0.9%) opportunistic infections among 4,135 patients allocated to anti-TNFα therapy, compared with 9 (0.3%) among 2,919 assigned to placebo. Among patients receiving active therapy these included eight cases of Mycobacterium tuberculosis, eight cases of herpes simplex infection, six cases of oral or esophageal candidiasis, six cases of herpes zoster infection, two cases of varicella-zoster virus infection, two cases of cytomegalovirus or Epstein-Barr virus infection, and one case of Nocardia infection. The RR of developing an opportunistic infection was significantly higher with anti-TNFα therapy (2.05; 95% CI 1.10-3.85, NNH=500; 95% CI 200-1,567). The RR of tuberculosis infection was 2.52 (95% CI 0.62-10.21).

CONCLUSIONS:

Anti-TNF therapy doubles the risk of opportunistic infections in inflammatory bowel disease patients. This underlines the importance of adherence to guidelines for their prevention and management.Am J Gastroenterol advance online publication, 7 May 2013; doi:10.1038/ajg.2013.138.

OBJECTIVES:

Nonpolypoid colorectal neoplasms (NP-CRNs) are proposed as a major contributor to the occurrence of interval cancers, but their underlying biology remains controversial. We conducted a systematic review and meta-analysis to clarify the major biological events in NP-CRNs.

METHODS:

We systematically searched for studies examining molecular characteristics of NP-CRNs. We performed random effect meta-analyses. We measured the heterogeneity among studies using I(2) and possible publication bias using funnel plots.

RESULTS:

Fifty-three studies on KRAS, APC, or BRAF mutations, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), or DNA promoter hypermethylation were included. We observed less KRAS mutations (summary odds ratio (OR) 0.30, confidence interval (CI)=0.19-0.46, I(2)=77.4%, CI=70.1-82.9) and APC mutations (summary OR 0.42, CI=0.24-0.72, I(2)=22.6%, CI=0.0-66.7) in NP-CRNs vs. protruded CRNs, whereas BRAF mutations were more frequent (summary OR 2.20, CI=1.01-4.81, I(2)=0%, CI=0-70.8), albeit all with large heterogeneity. Less KRAS mutations were especially found in NP-CRNs subtypes: depressed CRNs (summary OR 0.12, CI=0.05-0.29, I(2)=0%, CI=0-67.6), non-granular lateral spreading tumors (LSTs-NG) (summary OR 0.61, CI=0.37-1.0, I(2)=0%, CI=0-74.6), and early nonpolypoid carcinomas (summary OR 0.11, CI=0.06-0.19, I(2)=0%, CI=0-58.3). MSI frequency was similar in NP-CRNs and protruded CRNs (summary OR 0.99, CI=0.21-4.71, I(2)=70.3%, CI=38.4-85.7). Data for promoter hypermethylation and CIMP were inconsistent, precluding meaningful conclusions.

CONCLUSIONS:

This meta-analysis provides indications that NP-CRNs are molecularly different from protruded CRNs. In particular, some subtypes of NP-CRNs, the depressed and LST-NG, are featured by less KRAS mutations than polypoid CRNs. Prospective, multicenter studies are needed to clarify the molecular pathways underlying nonpolypoid colorectal carcinogenesis and potential implications for surveillance intervals.Am J Gastroenterol advance online publication, 7 May 2013; doi:10.1038/ajg.2013.126.

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal (GI) tract characterized by pain or discomfort from the lower abdominal region, which is associated with altered bowel habit. Despite its prevalence, there is currently a lack of effective treatment options for patients. IBS has long been considered as a neurological condition resulting from alterations in the brain gut axis, but immunological alterations are increasingly reported in IBS patients, consistent with the hypothesis that there is a chronic, but low-grade, immune activation. Mediators released by immune cells act to either dampen or amplify the activity of GI nerves. Release of a number of these mediators correlates with symptoms of IBS, highlighting the importance of interactions between the immune and the nervous systems. Investigation of the role of microbiota in these interactions is in its early stages, but may provide many answers regarding the mechanisms underlying activation of the immune system in IBS. Identifying what the key changes in the GI immune system are in IBS and how these changes modulate viscerosensory nervous function is essential for the development of novel therapies for the underlying disorder.Am J Gastroenterol advance online publication, 7 May 2013; doi:10.1038/ajg.2013.120.