C. J. J. Mulder

Thiopurine therapy in inflammatory bowel disease patients: Analyses of two 8-year intercept cohorts†

Background: Thiopurines have proven efficacy in long‐term maintenance therapy of inflammatory bowel disease (IBD). Limited data are available with regard to factors predicting effectiveness and failure of long‐term thiopurine use in IBD patients. Methods: The data in this retrospective study are based on an 8‐year intercept cohort of previous or present thiopurine‐using IBD patients. Both cohorts are assessed by descriptive and statistical analysis aimed at determining thiopurine effectiveness and the variables that are predictive for failure of thiopurine therapy. Results: In all, 363 IBD patients were included (60% female), 63% with Crohns disease and 33% with ulcerative colitis. Overall, thiopurines were continued in 145/363 (40%) and discontinued in 208/363 (57%) patients. The proportion of patients still using thiopurines at 3, 6, 12, 24, and 60 months was 73%, 69%, 63%, 51%, and 42%, respectively. Patients discontinued thiopurines due to adverse events (39%), refractoriness (16%), and ongoing remission / patients request (4%). 6‐methylmercaptopurine (6‐MMP) concentration and 6‐MMP/6‐thioguanine nucleotides (6‐TGN) ratio were significant higher in the failure group. Prolonged continuation of thiopurines was associated with a decreased risk of discontinuation. Conclusions: Azathioprine and 6‐mercaptopurine were considered effective in ≈40% of IBD patients after 5 years of treatment. A quarter of the patients discontinued thiopurines within 3 months, mostly due to adverse events. A high 6‐MMP concentration or 6‐MMP/6‐TGN ratio was associated with therapeutic failure. If thiopurine use was successfully initiated in the first months, its use was usually extended over many years, as long‐term use was associated with continuation of therapy. (Inflamm Bowel Dis 2010)

Flexible endoscopic treatment of zenker's diverticulum; A new approach

BACKGROUND AND STUDY AIMS In the past, a number of treatment modalities have been used for the management of a Zenkers diverticulum. These include transcervical diverticulectomy, myotomy, or laser or diathermy treatment via rigid endoscopes. Up to the present, no reports of the treatment of a Zenkers diverticulum with a flexible endoscope have been published. PATIENTS AND METHODS In this study, we present the results of our first 20 patients (13 male; mean age 82 years) prospectively treated with a flexible endoscope applied through diathermy. All patients had significant symptoms such as dysphagia, recurrent aspiration pneumonia and/or weight loss. RESULTS Treatment using a mean of three sessions per patient was successful, with a good symptomatic response in all subjects. There were no severe complications associated with the therapy. Four patients complained about a sore throat for a few days. During follow-up (mean 6-7 months), three patients died due to unrelated causes, and 17 remained asymptomatic. CONCLUSIONS An important advantage is that it is possible to perform the treatment without general anesthesia, and therefore also in patients whose general health is poor. The technique can easily be performed in an interventional endoscopy unit. Our first experiences show that flexible endoscopic treatment is an effective and relatively safe method.

Colonic work-up after incomplete colonoscopy: significant new findings during follow-up

BACKGROUND AND STUDY AIMS Cecal intubation is not achieved in 2 - 23 % of colonoscopies. The efforts made by physicians to visualize the remaining colon and the number of missed significant lesions are unknown. This study evaluates 1) the reasons for incomplete colonoscopy, 2) the rates of complete colonic evaluation after incomplete colonoscopy, and 3) the number of (pre-) malignant lesions missed by incomplete colonoscopy. PATIENTS AND METHODS In this population-based cohort study index colonoscopies were performed between September and December 2005. Prospectively collected data from consecutive patients with an incomplete colonoscopy were analyzed. For up to 18 months after the index colonoscopy, any further examinations performed in these patients were identified retrospectively. These secondary examinations included: repeat colonoscopy, computed tomography (CT) colonography, barium enema, abdominal CT scan, and surgery involving the colorectum. RESULTS Of 5278 colonoscopies, 511 were incomplete (9.7 %). The most frequent causes of incomplete colonoscopy were looping of the scope (20.4 %), patient discomfort (15.3 %), and obstructing tumor (13.9 %). Secondary examination was performed in 278 patients (54.4 %) after incomplete colonoscopy. Patients undergoing surveillance after colorectal cancer (CRC) (78.9 %) and those with anemia (73.1 %) most frequently received a secondary examination. Incomplete colonoscopies due to stenosis (78.9 %), severe inflammation (77.8 %) or an obstructing tumor (74.6 %) were most frequently followed by a secondary examination. In all of the follow-up examinations, CRC was diagnosed in 18 patients (3.5 %) and advanced adenoma in four patients (0.8 %). CONCLUSIONS In 4.3 % of the patients, advanced neoplasia was missed by incomplete colonoscopy. Our data therefore suggest that additional imaging is obligatory to visualize the remaining colon adequately.

Colonoscopy-controlled intra-individual comparisons to screen relevant neoplasia: faecal immunochemical test vs. guaiac-based faecal occult blood test.

Aliment Pharmacol Ther 31, 432–439

The citrulline generation test: proposal for a new enterocyte function test

Background  The amino acid citrulline is mainly produced by enterocytes from conversion of glutamine. As fasting plasma citrulline proved disappointing as a biomarker for enterocyte dysfunction in clinical practice, we propose a citrulline generation test (CGT) to assess enterocyte function.

Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands

Abstract Background and aims. Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). Methods. Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. Results. The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3–19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5–2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1–44 years). Familial occurrence was reported in three cases. Conclusion. This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.

Influence of 5-aminosalicylic acid on 6-thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy

Background and purpose:  5‐aminosalicylate (5‐ASA) raises levels of 6‐thioguanine nucleotides (6‐TGN), the active metabolites of thiopurines such as azathioprine (AZA). Changes in levels of each individual TGN – 6‐thioguanosine mono‐, di‐ and triphosphate (6‐TGMP, 6‐TGDP, 6‐TGTP) – and of 6‐methylmercaptopurine ribonucleotides (6‐MMPR) after 5‐ASA are not known.

Recurrent acute biliary pancreatitis: the protective role of cholecystectomy and endoscopic sphincterotomy

BackgroundRecurrent attacks of acute biliary pancreatitis (RABP) are prevented by (laparoscopic) cholecystectomy. Since the introduction of endoscopic retrograde cholangiopancreaticography (ERCP), several series have described a similar reduction of RABP after endoscopic sphincterotomy (ES). This report discusses the different treatment options for preventing RABP including conservative treatment, cholecystectomy, ES, and combinations of these options as well as their respective timing. MethodsA search in PubMed for observational studies and clinical (comparative) trials published in the English language was performed on the subject of recurrent acute biliary pancreatitis and other gallstone complications after an initial attack of acute pancreatitis. ResultCholecystectomy and ES both are superior to conservative treatment in reducing the incidence of RABP. Cholecystectomy provides additional protection for gallstone-related complications and mortality. Observational studies indicate that cholecystectomy combined with ES is the most effective treatment for reducing the incidence of RABP attacks. ConclusionFrom the literature data it can be concluded that ES is as effective in reducing RABP as cholecystectomy but inferior in reducing mortality and overall morbidity. The combination of ES and cholecystectomy seems superior to either of the treatment methods alone. A prospective randomized clinical trial comparing ES plus cholecystectomy with cholecystectomy alone is needed.

Higher Fecal Immunochemical Test Cutoff Levels: Lower Positivity Rates but Still Acceptable Detection Rates for Early-Stage Colorectal Cancers

Background: Adjusting the threshold for positivity of quantitative fecal immunochemical tests (FIT) allows for controlling the number of follow-up colonoscopies in a screening program. However, it is unknown to what extent higher cutoff levels affect detection rates of screen-relevant neoplasia. This study aimed to assess the effect of higher cutoff levels of a quantitative FIT on test positivity rate and detection rate of early-stage colorectal cancers (CRC). Methods: Subjects above 40 years old scheduled for colonoscopy in 5 hospitals were asked to sample a single FIT (OC sensor) before colonoscopy. Screen-relevant neoplasia were defined as advanced adenoma or early-stage cancer (stage I and II). Positivity rate, sensitivity, and specificity were evaluated at increasing cutoff levels of 50 to 200 ng/mL. Results: In 2,145 individuals who underwent total colonoscopy, 79 patients were diagnosed with CRC, 38 of which were with early-stage disease. Advanced adenomas were found in 236 patients. When varying cutoff levels from ≥50 to ≥200 ng/mL, positivity rates ranged from 16.5% to 10.2%. With increasing cutoff levels, sensitivity for early-stage CRCs and for screen-relevant neoplasia ranged from 84.2% to 78.9% and 47.1% to 37.2%, respectively. Conclusions: Higher FIT cutoff levels substantially decrease test positivity rates with only limited effects on detection rates of early-stage CRCs. However, spectrum bias resulting in higher estimates of sensitivity than would be expected in a screening population may be present. Impact: Higher cutoff levels can reduce strain on colonoscopy capacity with only a modest decrease in sensitivity for curable cancers. Cancer Epidemiol Biomarkers Prev; 20(2); 272–80. ©2010 AACR.

The effect of NOD2 activation on TLR2-mediated cytokine responses is dependent on activation dose and NOD2 genotype

The mechanism by which mutations in NOD2 predispose to Crohns disease (CD) is incompletely understood. In mice, NOD2 has been found to function as a negative regulator of Toll-like receptor 2 (TLR2) signaling. In contrast, studies in humans so far showed no negative regulatory interaction between NOD2 and TLR2, and in fact suggest a synergistic effect between the two. Here, we show that this interaction is dose dependent. Adding low doses of muramyl dipeptide (MDP) to TLR2 primed monocytes results in a significant increase in cytokine production, whereas adding higher doses of MDP led to a striking downregulation of the responses. This downregulation by high-dose MDP does not occur in monocytes from NOD2-deficient patients. The inhibitory role of NOD2 at high concentrations of MDP implicates a safety mechanism to prevent exaggerated antibacterial immune responses in the gut to high or perpetuating bacterial load. This regulatory mechanism is lost in NOD2-deficient CD patients.