What is the significance of the Hill classification?

This study aimed to investigate the significance of Hill classification to predict esophagitis, Barrett's esophagus, gastroesophageal reflux disease (GERD) symptomatology, and future prescriptions of proton pump inhibitors in clinical practice. A total of 922 patients (546 women and 376 men; mean age 54.3 [SD 18.4] years) who underwent gastroscopy between 2012 and 2015 were analyzed. Patient questionnaire regarding symptoms were compared with endoscopy findings. A medical chart review was done that focused on the prescription of PPIs, additional gastroscopies, and GERD surgery in a 3-year period before the index gastroscopy and in a 6-year period afterward. In patients naïve to PPI prescriptions (n = 466), Hill grade III was significantly associated with esophagitis (AOR 2.20; 95% CI 1.00-4.84) and > 2 PPI prescriptions 6 year after the index gastroscopy (AOR 1.95; 95% CI 1.01-3.75), whereas Hill grade IV was significantly associated with esophagitis (AOR 4.41; 95% CI 1.92-10.1), with Barrett's esophagus (AOR 12.7; 95% CI 1.45-112), with reported heartburn (AOR 2.28; 95% CI 1.10-4.74), and with >2 PPI prescriptions (AOR 2.16; 95% CI 1.02-4.55). In patients 'non-naïve' to PPI prescription (n = 556), only Hill grade IV was significantly associated with esophagitis, reported heartburn, and with >2 PPI prescriptions. The gastroscopic classification in Hill grades III and IV is important in clinical practice because they are associated with esophagitis, Barrett's esophagus, symptoms of GERD, and prescriptions of PPIs, whereas a differentiation between Hill grades I and II is not.

Persisting symptoms after Cryptosporidium hominis outbreak: a 10-year follow-up from Östersund, Sweden.

In late 2010, an outbreak of Cryptosporidium hominis affected 27,000 inhabitants (45%) of Östersund, Sweden. Previous research shows that abdomen and joint symptoms commonly persist up to 5 years post-infection. It is unknown whether Cryptosporidium is associated with sequelae for a longer duration, how persisting symptoms present over time, and whether sequelae are associated with prolonged infection. In this prospective cohort study, a randomly selected cohort in Östersund was surveyed about cryptosporidiosis symptoms in 2011 (response rate 69.2%). A case was defined as a respondent reporting new diarrhoea episodes during the outbreak. Follow-up questionnaires were sent after 5 and 10 years. Logistic regressions were used to examine associations between case status and symptoms reported after 10 years, with results presented as adjusted odds ratios (aOR) with 95% confidence intervals. Consistency of symptoms and associations with case status and number of days with symptoms during outbreak were analysed using X2 and Mann-Whitney U tests. The response rate after 10 years was 74% (n = 538). Case status was associated with reporting symptoms, with aOR of ~3 for abdominal symptoms and ~2 for joint symptoms. Cases were more likely to report consistent symptoms. Cases with consistent abdominal symptoms at follow-up reported 9.2 days with symptoms during the outbreak (SD 8.1), compared to 6.6 days (SD 6.1) for cases reporting varying or no symptoms (p = 0.003). We conclude that cryptosporidiosis was associated with an up to threefold risk for reporting symptoms 10 years post-infection. Consistent symptoms were associated with prolonged infection.

Systemic Inflammation in Preclinical Ulcerative Colitis.

BACKGROUND & AIMS: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. METHODS: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. RESULTS: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1ß, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. CONCLUSIONS: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.

Pre-diagnostic faecal calprotectin levels in patients with colorectal cancer: a retrospective study.

BACKGROUND: Faecal calprotectin (FC) is a potential biomarker for colorectal cancer (CRC) screening. There is uncertainty if tumor characteristics are associated with FC levels. We investigated how tumor stage and tumor localization influence the extent of FC levels in patients with CRC in clinical practice. METHODS: In two cohorts of patients with CRC, we retrospectively analyzed FC tests (CALPRO®) performed within three months prior to diagnosis. One hundred twenty-four patients with CRC were included (mean age 68 years, 44% women). RESULTS: Ninety-eight patients with CRC (79%) had a FC ≥ 50 µg/g. FC correlated positively with tumor stage (UICC based on WHO TNM classification) (rs 0.24; p = 0.007) and with CRP levels (rs 0.31, p = 001), and a negatively with B-haemoglobin (rs -0.21; p = 0.019). The patients with right-sided CRC had significantly more often a FC ≥ 50 µg/g than patients with left-sided CRC (92% vs 74% p = 0.027). In a binary logistic regression analysis, tumor stage III/IV (adjusted OR 3.47; CI 1.27-9.42) and right-sided tumor localization (adjusted OR 3.80; CI 1.01-14.3) were associated with FC ≥ 50 µg/g. Tumor stage III/IV (adjusted OR 2.30; CI 1.04-5.10) and acetylsalicylic use (adjusted OR 3.54; CI 1.03-12.2) were associated with FC ≥ 100 µg/g. In a cox regression analysis, a FC ≥ 100 µg/g was not associated with survival (Hazard OR 0.61; CI 0.24-1.52). CONCLUSIONS: Elevated pre-diagnostic FC levels were common in patients with CRC in close proximity to diagnosis. Right-sided localization and tumor stage were significantly associated with a rise in FC levels.

A more frequent disease monitorering but no increased disease activity in patients with inflammatory bowel disease during the first year of the SARS-CoV-2 pandemic. A retrospective study.

BACKGROUND AND AIMS: The SARS-CoV-2 pandemic abruptly switched the healthcare service for patients with inflammatory bowel disease (IBD) towards a telemedicine dominated approach. The aim of this study was to investigate the impact of this switch on monitoring of patients and on disease activity. MATERIAL: The pre-pandemic year included 868 patients and the first year of the pandemic included 891 patients. Medical records were retrospectively checked for contacts, changes in medical treatment, performed fecal calprotectin (FC) tests and colonoscopies. RESULTS: The scheduled follow-up visits to a doctor for patients with IBD shifted from mostly face-to-face pre-pandemic (from 389 to 118 appointments) to mostly telephone-based during the pandemic (from 13 to 423 appointments). There was a 21.3% increase in mean overall scheduled health contacts (p < .001) and a 20.0% increase for the mean number of FC tests (p < .001) in the year of the pandemic compared to the pre-pandemic year. The proportion of patients who had a surveillance colonoscopy was significant lower in the year of the pandemic compared to the pre-pandemic year (12.7% vs 20.1%; p = .002). There were no difference in the proportion of patients with a median FC > 200 mg/kg (18.2% vs 17.1%; p = .767) and in the proportion of patients who changed their medical treatment (24.7% vs 23.9%; p = .713) in the first year of the pandemic compared to the prepandemic year. CONCLUSIONS: The shift towards a telemedicine oriented IBD healthcare service in the first year of the pandemic significantly increased the scheduled contacts, as well as the frequency of FC testing. However, there was a significant decrease in performed surveillance colonoscopies. Between the two periods observed, the patients showed no difference in medical treatment or in disease activity.

Increased incidence of late-onset inflammatory bowel disease and microscopic colitis after a Cryptosporidium hominis outbreak.

OBJECTIVES: In 2010, 27,000 inhabitants (45% of the population) of Östersund, Sweden, contracted clinical cryptosporidiosis after drinking water contaminated with Cryptosporidium hominis. After the outbreak, local physicians perceived that the incidence of inflammatory bowel disease (IBD), including ulcerative colitis (UC), Crohn's disease (CD), and IBD-unclassified, and microscopic colitis (MC) increased. This study assessed whether this perception was correct. MATERIALS AND METHODS: This observational study included adult patients (≥18 years old) from the local health care region who were diagnosed with pathology-confirmed IBD or MC during 2006-2019. We collected and validated the diagnosis, date of diagnosis, age at diagnosis, and sex from the Swedish quality register SWIBREG and electronic patient records. Population data were collected from Statistics Sweden. The incidences for 2006-2010 (pre-outbreak) and 2011-2019 (post-outbreak) were evaluated by negative binomial regression analysis and presented as incidence rate ratios (IRRs). Data were analyzed for IBD, for UC and CD separately, and MC. RESULTS: During the study period, we identified 410 patients with new onset IBD and 155 new cases of MC. Overall, we found a trend toward an increased incidence of IBD post-outbreak (IRR 1.39, confidence interval (CI) 0.99-1.94). In individuals ≥40 years old, the post-outbreak incidence significantly increased for IBD (IRR 1.69, CI 1.13-2.51) and CD (IRR 2.23, CI 1.08-4.62). Post-outbreak incidence of MC increased 6-fold in all age groups (IRR 6.43, CI 2.78-14.87). CONCLUSIONS: The incidence of late-onset IBD and MC increased after the Cryptosporidium outbreak. Cryptosporidiosis may be an environmental risk factor for IBD and MC.

Self-monitoring with home based fecal calprotectin is associated with increased medical treatment. A randomized controlled trial on patients with inflammatory bowel disease.

OBJECTIVES: Self-monitoring of inflammatory bowel disease (IBD) with the assistant of telemedicine and home-based fecal calprotectin (FC) tests is evolving in the management of IBD. We performed a randomized controlled trial to investigate the compliance and effects of the model IBD-Home in patients with IBD. MATERIALS AND METHODS: Patients were randomized to IBD-Home + standard care (n = 84) or standard care alone (n = 74). Intervention with IBD-Home included IBDoc® FC test kits and a digital application used for answering symptom questionnaires (Abbvie/Telia). They were instructed to use these on demand during a 12-month period. Data was collected retrospectively from medical records. Patients who completed the intervention were phoned and asked to answer a survey about the experience of IBD-Home. RESULTS: The compliance to IBD-Home was low (29%). Women were more compliant compared with men (43% vs 17%, p < .001). A significantly higher proportion of patients in the IBD-Home group increased their medical treatment during the study period in comparison to control subjects (33% vs 15% p = .007) and there was an association between an increase in treatment and compliance to IBD home (multivariate odds ratio 3.22; 95th confidence interval 1.04 - 9.95). Overall patients reported a positive experience with slight technical difficulties. CONCLUSION: Self-monitoring with home based fecal calprotectin and a digital application was found feasible and appreciated by compliers. Compliance to the IBD-Home model was more common in women and associated with an increased treatment for IBD.

Increased chronic pain in patients with ulcerative colitis is mostly associated to increased disease activity. A cross-sectional case-control study.

BACKGROUNDS/AIMS: Musculoskeletal symptoms are common in patients with ulcerative colitis (UC), but no study has compared the prevalence of chronic pain to controls from a general population. METHODS: Patients with UC (n = 1164) and controls (n = 3867) were sent questionnaires comprising demography, history of pain, pain localization and UC patients' Patient-Simple Clinical Colitis Activity Index. Chronic regional pain (ChRP) and chronic widespread pain (ChWP) were defined as having pain for at least 3 months. RESULTS: The response rate for the patients with UC was 49.0% and for the control persons 61.7% (p < .001). The reported prevalence of ChRP and ChWP was higher in patients with UC versus controls (33.1% vs. 24.2%; p < .001 and 19.8% vs. 12.5%; p < .001). The patients with UC reported significantly more pain in the regions 'lower back', 'hip/upper leg' and 'lower leg/foot' compared to controls. The patients with P-SCCAI ≥ 5 (n = 121) reported more ChWP than patients with P-SCCAI <5 (n = 426) (46.3% vs. 12.7%; p < .001) and controls (n = 2425) (46.3 vs. 12.5%; p < .001) in all body regions. No significant difference in ChWP was found between patients with P-SCCAI <5 and controls (12.7% vs. 12.5%; p = .917). CONCLUSIONS: Patients with UC reported more chronic pain than controls from the general population, especially from the lower back and hip region. Higher UC disease activity was associated with more pain in all body regions.

The use of ICD codes to identify IBD subtypes and phenotypes of the Montreal classification in the Swedish National Patient Register.

Introduction: Whether data on International Classification of Diseases (ICD)-codes from the Swedish National Patient Register (NPR) correctly correspond to subtypes of inflammatory bowel disease (IBD) and phenotypes of the Montreal classification scheme among patients with prevalent disease is unknown.Materials and methods: We obtained information on IBD subtypes and phenotypes from the medical records of 1403 patients with known IBD who underwent biological treatment at ten Swedish hospitals and retrieved information on their IBD-associated diagnostic codes from the NPR. We used previously described algorithms to define IBD subtypes and phenotypes. Finally, we compared these register-generated subtypes and phenotypes with the corresponding information from the medical records and calculated positive predictive values (PPV) with 95% confidence intervals.Results: Among patients with clinically confirmed disease and diagnostic listings of IBD in the NPR (N = 1401), the PPV was 97 (96-99)% for Crohn's disease, 98 (97-100)% for ulcerative colitis, and 8 (4-11)% for IBD-unclassified. The overall accuracy for age at diagnosis was 95% (when defined as A1, A2, or A3). Examining the validity of codes representing disease phenotype, the PPV was 36 (32-40)% for colonic Crohn's disease (L2), 61 (56-65)% for non-stricturing/non-penetrating Crohn's disease behaviour (B1) and 83 (78-87)% for perianal disease. Correspondingly, the PPV was 80 (71-89)% for proctitis (E1)/left-sided colitis (E2) in ulcerative colitis.Conclusions: Among people with known IBD, the NPR is a reliable source of data to classify most subtypes of prevalent IBD, even though misclassification commonly occurred in Crohn's disease location and behaviour and also among IBD-unclassified patients.

Patient-reported and doctor-reported symptoms when faecal immunochemical tests are requested in primary care in the diagnosis of colorectal cancer and inflammatory bowel disease: a prospective study.

BACKGROUND: Rectal bleeding and a change in bowel habits are considered to be alarm symptoms for colorectal cancer and they are also common symptoms for inflammatory bowel disease. However, most patients with these symptoms do not have any of these diseases. Faecal immunochemical tests (FITs) for haemoglobin are used as triage tests in Sweden and other countries but little is known about the symptoms patients have when FITs are requested. OBJECTIVE: Firstly, to determine patients' symptoms when FITs are used as triage tests in primary care and whether doctors record the symptoms that patients report, and secondly to evaluate the association between symptoms, FIT results and possible prediction of colorectal cancer or inflammatory bowel disease. METHODS AND MATERIALS: This prospective study included 364 consecutive patients for whom primary care doctors requested a FIT. Questionnaires including gastrointestinal symptoms were completed by patients and doctors. RESULTS: Concordance between symptoms reported from patients and doctors was low. Rectal bleeding was recorded by 43.5% of patients versus 25.6% of doctors, FITs were negative in 58.3 and 52.7% of these cases respectively. The positive predictive value (PPV) of rectal bleeding recorded by patients for colorectal cancer or inflammatory bowel disease was 9.9% (95% confidence interval [CI] 5.2-14.7); for rectal bleeding combined with a FIT the PPV was 22.6% (95% CI 12.2-33.0) and the negative predictive value (NPV) was 98.9% (95% CI 96.7-100). For patient-recorded change in bowel habits the PPV was 6.1% (95% CI 2.4-9.8); for change in bowel habits combined with a FIT the PPV was 18.2% (95% CI 9.1-30.9) and the NPV 100% (95% CI 90.3-100). CONCLUSIONS: Doctors should be aware that, during consultations, they do not record all symptoms experienced by patients. FITs requested in primary care, when found positive, may potentially be of help in prioritising referrals, also when patients present with rectal bleeding or change in bowel habits.

Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

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.

Swedish Inflammatory Bowel Disease Register (SWIBREG) - a nationwide quality register.

Background: Inflammatory bowel disease (IBD) is a chronic, inflammatory relapsing disease with increasing incidence. IBD research and long-term follow-up of patients have, however, been hampered by lack of detailed data on disease phenotype, patient-reported outcome measures, Physician Global Assessment, disease activity, and hospital-administered drugs. Aim: To review the Swedish IBD quality register (SWIBREG). Methods: Review of SWIBREG including questionnaire data from users and patients. Results: SWIBREG was launched in 2005, and as of April 2019, contains 46,400 patients with IBD (Crohn's disease: n = 15,705, ulcerative colitis: n = 21,540, IBD unclassified and other colitis (including e.g., microscopic colitis): n = 9155). Of these IBD patients, 7778 had been diagnosed in childhood (16.8%). Earlier research has shown that combining SWIBREG and the Swedish National Patient Register (NPR) yields a positive predictive value of 100% (95%CI = 95-100%) for having a diagnosis of IBD. Moreover, out of all patients in the NPR with a diagnosis of IBD plus either IBD-related surgery or immunomodulatory/biological treatment during the past 18 months, SWIBREG covers 59.0%. SWIBREG records not only information on conventional therapies but also on biological treatment, surgery, smoking, disease activity, patient-reported outcome measures (PROMs), and patient-experienced measures (PREMs). Data are presented through a graphical decision support system. Conclusion: SWIBREG benefits patients with IBD, and offers an ideal opportunity for healthcare personnel and researchers to examine disease phenotype and activity, PROMs/PREMs, and hospital-administered drugs in patients with IBD.

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.

Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.

OBJECTIVE: IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. DESIGN: We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. RESULTS: CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). CONCLUSIONS: SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients.

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).

Smoking is associated with risk for developing inflammatory bowel disease including late onset ulcerative colitis: a prospective study.

OBJECTIVES: Life style factors have been associated with inflammatory bowel disease (IBD) but there is a lack of data on the exposure of life styles factors before the onset of IBD. Our aim was to study the association between lifestyle factors and the development of IBD in a prospective setting. MATERIALS AND METHODS: We performed a case control study of 72 patients who later developed ulcerative colitis (UC), 26 patients who developed Crohn's disease (CD) and 427 healthy controls from the Västerbotten intervention project matched for gender, age, year of health survey and area of residence. At recruitment, participants completed validated lifestyle questionnaires including data on alcohol intake. Information from this was used to assess the connection between lifestyle factors and later developing IBD. RESULTS: For CD and UC, the median age at diagnosis was 53 and 52 years and median time of survey was 4 and 6 years before diagnosis, respectively. Multivariate odds ratio (OR) showed an association between never smoking and not developing IBD, including both UC and CD, OR (95% CI) 0.341 (0.136-0.853) and 0.473 (0.259-0.864), respectively. Marital status, educational level, alcohol consumption, reported physical activity and use of moist smokeless tobacco (snus) did not differ between patients and controls. CONCLUSIONS: Smoking proves to be a risk factor for both CD and UC in this prospective case-control study. No association was seen for snus users, implying a non-nicotine pathogenic mechanism from combusted tobacco.

Cancer-associated fecal microbial markers in colorectal cancer detection.

Colorectal cancer (CRC) is the second most common cause of cancer death in the western world. An effective screening program leading to early detection of disease would severely reduce the mortality of CRC. Alterations in the gut microbiota have been linked to CRC, but the potential of microbial markers for use in CRC screening has been largely unstudied. We used a nested case-control study of 238 study subjects to explore the use of microbial markers for clbA+ bacteria harboring the pks pathogenicity island, afa-C+ diffusely adherent Escherichia coli harboring the afa-1 operon, and Fusobacterium nucleatum in stool as potential screening markers for CRC. We found that individual markers for clbA+ bacteria and F. nucleatum were more abundant in stool of patients with CRC, and could predict cancer with a relatively high specificity (81.5% and 76.9%, respectively) and with a sensitivity of 56.4% and 69.2%, respectively. In a combined test of clbA+ bacteria and F. nucleatum, CRC was detected with a specificity of 63.1% and a sensitivity of 84.6%. Our findings support a potential value of microbial factors in stool as putative noninvasive biomarkers for CRC detection. We propose that microbial markers may represent an important future screening strategy for CRC, selecting patients with a "high-risk" microbial pattern to other further diagnostic procedures such as colonoscopy.

Diagnosing colorectal cancer and inflammatory bowel disease in primary care: The usefulness of tests for faecal haemoglobin, faecal calprotectin, anaemia and iron deficiency. A prospective study.

OBJECTIVE: Abdominal complaints are common reasons to consult primary care but they are seldom caused by colorectal cancer (CRC), high-risk adenomas (HRAs), or inflammatory bowel disease (IBD). Reliable diagnostic aids would be helpful in deciding which patients to refer for bowel imaging. Our aim was to assess the value of a faecal immunochemical test (FIT) and a faecal calprotectin (FC) test in detecting CRC, HRAs and IBD in primary care, and the value of combining these tests with anaemia and iron-deficiency tests. MATERIALS AND METHODS: This prospective study included 373 consecutive patients that received a FIT or a FC test ordered by a primary care physician. We collected samples for FITs, FC tests, full blood counts and iron-deficiency tests. Physicians were instructed to refer patients with a positive FIT or FC test (cut-off ≥100µg/g) for bowel imaging. The patients' presenting symptoms were recorded. Patients were followed for 2 years. RESULTS: The best test for detecting CRC and IBD was the combination of the FIT and haemoglobin concentration. This test had a sensitivity, specificity, positive predictive value and negative predictive value of 100%, 61.7%, 11.7% and 100%, respectively. The FIT detected a significantly larger proportion of CRC, HRAs and IBD than the FC test (0.92 versus 0.46, 95% confidence interval 0.22-0.67). CONCLUSION: A negative FIT combined with a normal haemoglobin concentration could rule out CRC and IBD with a high degree of safety. This could be useful in prioritising referrals for bowel imaging from primary care.

Radiation exposure in patients with inflammatory bowel disease and irritable bowel syndrome in the years 2001-2011.

OBJECTIVES: To compare cumulative ionizing radiation in patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) for the years 2001-2011. To study how radiation exposure change over time in patients with newly diagnosed IBD and factors associated with radiation exposure. MATERIAL AND METHODS: All radiological investigations performed between 1 January 2001 and 31 December 2011 were retrospectively recorded in patients with Crohn's disease (CD) (n = 103), ulcerative colitis (UC) (n = 304) and IBS (n = 149). Analyses were done with Mann-Whitney and Chi-Square test. RESULTS: The median total cumulative radiation exposure in mSv for CD (20.0, inter quartile range (IQR) 34.8), UC (7.01, IQR 23.8), IBS (2.71, IQR 9.15) and the proportion of patients who had been exposed for more than 50 mSv during the study period (CD 19%, UC 11%, IBS 3%) were significantly higher in the patients with CD compared to patients with UC (p < .001) and IBS (p < .001), respectively. In turn, patients with UC had significantly higher doses than patients with IBS (p = .005). Risk factors for radiation exposure were female gender (CD), early onset (UC), ileocolonic location (CD), previous surgery (CD and UC), depression (IBS) and widespread pain (IBS). In newly diagnosed CD, there was a significant decline in median cumulative radiation dose in mSv (17.2 vs. 12.0; p = .048) during the study period. CONCLUSIONS: Patients with CD are at greatest risk for high cumulative radiation exposure, but there is a decline in exposure during the late 2000s. Non-colectomized patients with UC and patients with IBS have a relatively low risk of cumulative radiation exposure.