Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy.

OBJECTIVES: Faecal Calprotectin (FC) is a sensitive marker for gut inflammation. However, slightly elevated FC levels are also common in subjects without inflammation. We investigated the association between FC and clinical factors including concomitant use of medical therapy in patients with a normal colonoscopy. MATERIAL AND METHODS: Out-patients (n = 1263) referred for colonoscopy, performed FC test (CALPRO) the day before the start of bowel preparation. All subjects answered questionnaires that included questions on the present and past health history, concomitant medical treatment and gastrointestinal symptoms (GSRS). A medical record chart review was performed to check for concomitant disease, cause of referral and the result of the colonoscopy including biopsies. Inclusion criteria were a normal colonoscopy. Exclusion criteria were inflammatory bowel disease, colon cancer and high-grade dysplasia. RESULTS: Five hundred ninety subjects fulfilled the inclusion criteria and completed the study. Thirty-six per cent of the subjects had a FC >50 µg/g. In a logistic regression analysis, age (adjusted OR: 1.051; CI: 1.032-1.071), and the use of proton pump inhibitors (adjusted OR: 3.843; CI: 2.338-6.316), non-steroid anti-inflammatory drugs (adjusted OR: 2.411; CI: 1.162-5.002) and acetylsalicylic acid (adjusted OR: 2.934; CI: 1.085-3.448) were significantly associated with an elevated FC (>50 µg/g). CONCLUSIONS: More than one-third of the patients with a normal colonoscopy performed in clinical routine had a slightly elevated FC level. Our results emphasise the need for attention to age, the use of proton pump inhibitors, non-steroid anti-inflammatory drugs and acetylsalicylic acid in the interpretation of FC tests in clinical practice.

Improved monitoring of inflammatory activity in patients with ulcerative colitis by combination of faecal tests for haemoglobin and calprotectin.

Faecal calprotectin (FC) tests and faecal immunological tests (FIT) for haemoglobin have been used to monitor disease activity in patients with ulcerative colitis (UC) but used alone they have some limitation concerning the predictive ability. We aimed to test if an FC test used in combination with FIT could improve the predictive ability. Consecutive out-patients with UC (n = 93) who were admitted for colonoscopy completed a single faecal sample before the start of bowel preparation. A quantitative CALPRO® calprotectin ELISA test and a qualitative FIT (cut-off < 40 ng/mL) were analyzed. An estimated Mayo score and a score of histological inflammation was performed blinded to the result of the faecal tests. The sensitivity, specificity, negative predictive value and positive predictive value for endoscopic inflammation (Mayo score > 1) was for FIT 85%, 83%, 96%, 57% and for FC > 186 µg/g 73%, 87%, 87%, 54%. Corresponding results for FIT*FC > 186 µg/g (at least one test positive) were 92%, 69%, 97%, 43%. For detecting moderate/severe histological inflammation the results were for FIT 69%, 79%, 92%, 43%, for FC > 75 µg/g 95%, 62%, 98%, 41%, and for FIT*FC > 75 µg/g 100%, 60%, 100%, 36%. None of the markers alone or in combination were useful to predict deep remission (Mayo score = 0 and no histological inflammation). We conclude that using the combination of an FC test and FIT shows minor improvement in predictive ability for inflammatory activity and remission in patients with UC.

Safety of azathioprine and 6-mercaptopurine in patients with inflammatory bowel disease naïve to thiopurine treatment
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OBJECTIVES: To determine if 6-mercaptopurine (MP) is better tolerated than azathioprine (AZA) as the initial thiopurine treatment in patients suffering from inflammatory bowel disease (IBD). Switching patients with IBD from AZA to MP is advocated in patients intolerant to AZA. However, no study has determined if MP is more suited than AZA as a first-line treatment for patients who are naïve to thiopurine treatment. STUDY: The tolerance of AZA and MP treatments in clinical practice was retrospectively evaluated from start to 12 months after initiating treatment in 113 patients with IBD who were all naïve to thiopurines (82 patients treated with AZA and 31 patients with MP). RESULTS: 65% of the patients treated with AZA and 61% of the patients treated with MP tolerated their treatment during 12 months (i.e., no group difference, p = 0.742). No difference in reported side effects between the two treatments was observed. The mean equivalent initial dose (0.92 vs. 0.61 mg/kg; p < 0.001) and the mean equivalent dose at 12 months (1.98 vs. 1.65 mg/kg; p = 0.014) was significantly higher in the MP group vs. the AZA group. The proportion of patients with ΔMCV ≥ 7 at 12 months was numerically higher in the MP group than in the AZA group (53% vs. 31%; p = 0.090). CONCLUSIONS: In this retrospective observational study, no differences in tolerance or adherence between AZA and MP were observed in patients naïve to thiopurines. However, MP treatment was at a higher equivalent thiopurine dose than AZA treatment, which tended to be associated with better treatment response.
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Preclinical Markers in Inflammatory Bowel Disease. A Nested Case-Control Study.

Background: Our objective was to determine if patients who later develop inflammatory bowel disease (IBD) show signs of increased inflammatory activity in plasma measured with high sensitivity C-reactive protein (CRP), calprotectin, and albumin before the clinical onset of IBD. Methods: We identified 96 subjects who later developed IBD (70 ulcerative colitis [UC] and 26 Crohn's disease [CD]). High sensitivity CRP, calprotectin, and albumin were analyzed in frozen plasma, donated from cases and sex-age matched controls 1-15 years before diagnosis. Results: We found that subjects who later developed UC had lower albumin levels, and subjects who later developed CD had higher CRP levels than controls. Multivariable conditional logistic regression with albumin, calprotectin, and CRP showed a lower risk for developing IBD and UC with higher albumin levels (odds ratio [OR] 0.79, confidence interval [CI] 0.69-0.90; respective OR 0.77, CI 0.66-0.91). Higher CRP levels were associated with an increased risk of developing CD (OR 1.314, CI 1.060-1.630). When adjusting for body mass index or smoking in the logistic regression model, similar results were found. Plasma calprotectin levels in the preclinical period among patients with IBD did not differ from controls. Conclusions: In this nested case-control study, subjects who later developed IBD had signs of low-grade systemic inflammation, indicated by significantly higher CRP plasma levels in CD and lower albumin plasma levels in UC, before the onset of clinical disease.

Elevated Faecal Calprotectin in Patients with a Normal Colonoscopy: Does It Matter in Clinical Practice? A Retrospective Observational Study.

INTRODUCTION: Faecal calprotectin (FC) is commonly used as a diagnostic tool for patients with gastrointestinal (GI) symptoms. However, there is uncertainty in daily clinical practice how to interpret an elevated FC in patients with a normal colonoscopy. We investigated if patients with a normal colonoscopy but with an elevated FC more often were diagnosed with a GI disease in a 3-year follow-up period. METHODS: Patients referred for colonoscopy (n = 1,263) to the Umeå University Hospital endoscopy unit between 2007 and 2013 performed a FC test (CALPRO®) on the day before bowel preparation. A medical chart review was performed on all patients who had normal findings on their colonoscopy (n = 585, median age 64 years). RESULTS: Thirty-four percent of the patients (n = 202) with normal colonoscopy had elevated FC (>50 µg/g), and these patients were more frequently diagnosed with upper GI disease during the follow-up period than patients with normal FC levels (9.9 vs. 4.7%; p = 0.015). The upper GI diseases were mainly benign (i.e., gastritis). In a binary logistic regression analysis controlling for age, gender, nonsteroid anti-inflammatory drug use, and proton-pump inhibitor use, there was no difference for a new diagnosis of upper GI disease in the follow-up period (multivariate OR 1.70; 95% CI: 0.77-3.74). There was no difference in a new diagnosis of lower GI disease (6.4 vs. 5.2%; p = 0.545) or cardiovascular disease/death (multivariate OR 1.68; 95% CI: 0.83-3.42) in the follow-up period between patients with elevated versus normal FC levels. CONCLUSIONS: In patients with a normal colonoscopy, a simultaneously measured increased FC level was not associated with an increased risk for significant GI disease during a follow-up period of 3 years.

[Low diagnostic accuracy of rigid sigmoidoscopy in the investigation of rectal cancer]. / Var femte rektalcancer missas efter rektoskopi i primärvården.

We performed a retrospective observational study to investigate the diagnostic accuracy of rigid sigmoidoscopy (RS) in patients with rectal cancer (n=279). Fifty-six percent of the patients had performed an RS within three months before diagnosis and mostly by a primary care provider (93%). In 21% of the patients the physician determined that the examination was normal, in 50% a rectal tumor was suspected and in 29% of cases an unspecific pathology (e.g. luminal blood, mucosal abnormalities) was reported. A normal finding on RS was associated with a longer time between the first appointment and subsequent diagnosis (multivariate hazard ratio (HR) 0.50; 95th percentile CI 0.35-0.71) whereas a history of rectal bleeding (multivariate HR 1.49; 95th percentile CI 1.01-2.20) and adherence to new national guidelines (multivariate HR 1.46; 95th percentile CI 1.08-1.99) was associated with a shorter time to diagnosis. We conclude that RS only had modest diagnostic accuracy in the diagnosis of rectal cancer, at least in this mainly primary care-based setting.

Irritable bowel syndrome-like symptoms in treated microscopic colitis patients compared with controls: a cross-sectional study.

BACKGROUND: The prevalence of irritable bowel syndrome (IBS)-like symptoms is high in untreated patients with microscopic colitis (MC), but there is uncertainty of the prevalence of IBS-like symptoms in treated patients. We assessed the degree of IBS-like symptoms in patients with MC in comparison to control subjects, and investigated the association between IBS-like symptoms and faecal calprotectin (FC) in MC patients. METHODS: Patients with an established MC diagnosis (n = 57) were compared to sex- and age-matched controls (n = 138) for scores in the GSRS-IBS (Gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome) and HADS (Hospital Anxiety Depression Scale). In MC patients, an FC level was simultaneously analysed. RESULTS: The median interval from MC diagnoses to the time the subjects participated in the study was 5.5 years (25th-75th percentiles; 4.5-9.5 years). The total GSRS-IBS score, subscores for abdominal pain, bloating, and diarrhoea were significantly higher in MC patients compared to controls (all P < 0.001). There was a significant correlation between FC levels and reported bowel frequency (P = 0.023), but there was no correlation between FC levels and GSRS-IBS scores. Patients with MC had significantly higher scores on anxiety (HADS-A) (P < 0.001) and used more selective serotonin-reuptake-inhibitor drugs (P = 0.016) than the control subjects. However, only the control subjects (not the patients with MC) showed significant correlations between GSRS-IBS scores and HADS scores. CONCLUSIONS: Patients with MC reported more IBS-like symptoms and anxiety than control subjects but neither FC levels nor symptoms of affectivity were significantly correlated with IBS-like symptoms.

The clinical course after glucocorticoid treatment in patients with inflammatory bowel disease is linked to suppression of the hypothalamic-pituitary-adrenal axis: a retrospective observational study.

BACKGROUND: Adrenal insufficiency (AI) secondary to treatment with glucocorticoids (GCs) is common in patients with inflammatory bowel disease (IBD), but little is known about the relationship between AI and the clinical course in IBD. The aim of the study was to compare the clinical course in IBD patients with normal adrenal function versus patients with subnormal adrenal function. METHODS: A retrospective observational study on 63 patients with IBD who had performed a low-dose short Synacthen test (LDSST) (1 µg) immediately (1-7 days) after a standard course of GCs. A subnormal LDSST was defined as serum cortisol <550 nmol/L. Outcomes were time to next flare and fecal calprotectin levels. RESULTS: Sixty-three percent (n = 40) of the IBD patients had a subnormal LDSST. Patients who were steroid-free (n = 41) after the LDSST were observed for 3 years. Patients with a peak serum cortisol <400 nmol/L immediately after GC treatment had significantly longer time until the next flare-up of their IBD and tended to use a lower cumulative prednisolone dose during the study period in comparison to the other subgroups. Fecal calprotectin levels were significantly lower in patients with a peak s-cortisol <550 nmol/L versus patients with peak s-cortisol ⩾550 nmol/L (median 336 µg/g (IQR 521) versus 955 µg/g (IQR 1867); p = 0.012). CONCLUSIONS: GC-induced AI is common in patients with IBD and is associated with lower disease activity. This suggests a link between responsiveness to GC treatment and suppression of the hypothalamic-pituitary-adrenal axis in IBD.

Lactosylceramide-induced apoptosis in primary amnion cells and amnion-derived WISH cells.

Amnion apoptosis is part of a programmed process of fetal membrane remodeling leading to weakening and rupture. The apoptotic agent lactosylceramide is elevated in amniotic fluid of premature infants with rupture of membranes. We have shown that apoptosis in WISH cells, induced by staurosporine, cycloheximide, or actinomycin D, can be blocked by cyclooxygenase inhibitors, suggesting a relationship between prostaglandin production and apoptosis. Cyclic adenosine monophosphate (cAMP) is known to inhibit prostaglandin release in amnion and WISH cells. This study was undertaken to determine the apoptotic potential of lactosylceramide and the effect of cyclooxygenase inhibitors and cAMP activators on lactosylceramide-induced apoptosis in primary amnion and WISH cells. Primary amnion cells and WISH cells were incubated with lactosylceramide to determine apoptosis and prostaglandin E(2) (PGE(2)) release. Apoptosis was confirmed by agarose gel electrophoretic DNA fragmentation analysis, nuclear matrix protein (NMP), and nucleosome enzyme-linked immunosorbent assay. In some studies, cells were preincubated with cyclooxygenase inhibitors or cAMP activators. Lactosylceramide induced a 20-fold increase in NMP (measure of cell death) in both cell types. Apoptosis was confirmed by the studies listed in methods. Lactosylceramide increased PGE(2) release in parallel with apoptosis. Cyclooxygenase inhibitors as well as cAMP activators inhibited both PGE(2) release and apoptosis. Lactosylceramide-induced apoptosis in both amnion and WISH cells. Parallel PGE(2) release was demonstrated with apoptosis. Cyclooxygenase inhibitors and cAMP activators blocked both processes.

Comparative stochastic effects of alpha, beta or x-irradiation of the lung of rats.

The stochastic effects in the lung of inhaled, insoluble particles of alpha- and beta-emitting particles and low-linear energy transfer (LET) thoracic irradiation were compared in rats using data from previously conducted studies. Male and female F344 rats were exposed briefly by nasal inhalation to relatively insoluble aerosols of CeO(2) or PuO(2) to achieve a range of four lung burdens. The mean lifetime beta doses to the lung were 3.6 + or - 1.3 Gy, 6.8 + or - 1.7 Gy, 12 + or - 4.5 Gy, and 37 + or - 5.9 Gy. The mean lifetime alpha doses to the lung were 0.06 + or - 0.03 Gy, 0.95 + or - 0.46 Gy, 3.7 + or - 1.6 Gy, and 12 + or - 2.4 Gy. Additional rats were exposed to fractionated thoracic doses of x rays given on 10 successive working days. The lifetime doses to the lung were 3.3 Gy, 5.7 Gy, 11 Gy, and 38 Gy. Appropriate sham controls were included in each group and all groups were observed for their life spans. Lung neoplasms were found after all exposures, with the incidence increasing with radiation dose. Rats exposed to PuO(2) had the highest incidence, 94% in the group with a dose of 12 Gy. The incidence in the groups exposed to inhaled CeO(2) or fractionated thoracic x-irradiation was not significantly different. The incidence of lung tumors in the PuO(2) groups was 21 times higher than that of the groups exposed to the lower LET radiations. These results support a radiation-weighting factor of 20, as recommended by ICRP 60.

A nonsense mutation of PEPD in four Amish children with prolidase deficiency.

Encoded by the peptidase D (PEPD) gene located at 19q12-q13.11, prolidase is a ubiquitous cytosolic enzyme that catalyzes hydrolysis of oligopeptides with a C-terminal proline or hydroxyproline. We describe here four Amish children with a severe phenotype of prolidase deficiency in the Geauga settlements of Ohio as the first report of prolidase deficiency in the Amish population as well as in the United States. The patients presented with infection, hepatosplenomegaly, or thrombocytopenia, in contrast to most cases previously reported in the literature, presenting with skin ulcers. All four patients had typical facial features, classic skin ulcers, and multisystem involvement. Recurrent infections, asthma-like chronic reactive airway disease, hyperimmunoglobulins, hepatosplenomegaly with mildly elevated aspartate transaminase (AST), anemia, and thrombocytopenia were common and massive imidodipeptiduria was universal. Prolidase activity in our patients is nearly undetectable. Direct sequencing of PCR-amplified genomic DNA for all of the exons from the four patients revealed the same homozygous single nucleotide mutation c.793 T > C in exon 11, resulting in a premature stop-codon at amino acid residue 265 (p.R265X). It is speculated that the severe phenotype in these patients might be associated with the type of the PEPD gene mutation.