| 1. |
- Appleby, R. N., et al.
(författare)
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Effects of conventional and a novel colonic-release bile acid sequestrant, A3384, on fibroblast growth factor 19 and bile acid metabolism in healthy volunteers and patients with bile acid diarrhoea
- 2017
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Ingår i: United European Gastroenterology Journal. - : Wiley. - 2050-6406 .- 2050-6414. ; 5:3, s. 380-388
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Tidskriftsartikel (refereegranskat)abstract
- Background: Primary bile acid diarrhoea (BAD) is associated with increased bile acid synthesis and low fibroblast growth factor 19 (FGF19). Bile acid sequestrants are used as therapy, but are poorly tolerated and may exacerbate FGF19 deficiency. Aim: The purpose of this study was to evaluate the pharmacological effects of conventional sequestrants and a colonic-release formulation preparation of colestyramine (A3384) on bile acid metabolism and bowel function in patients with BAD. Methods: Patients with seven-day (75)selenium-homocholic acid taurine (SeHCAT) scan retention <10% were randomised in a double-blind protocol to two weeks treatment with twice-daily A3384 250mg (n=6), 1g (n=7) or placebo (n=6). Thirteen patients were taking conventional sequestrants at the start of the study. Symptoms were recorded and serum FGF19 and 7 alpha-hydroxy-4-cholesten-3-one (C4) measured. Results: Median serum FGF19 on conventional sequestrant treatment was 28% lower than baseline values in BAD (p<0.05). C4 on conventional sequestrant treatment was 58% higher in BAD (p<0.001). No changes were seen on starting or withdrawing A3384. A3384 improved diarrhoeal symptoms, with a median reduction of 2.2 points on a 0-10 Likert scale compared to placebo, p<0.05. Conclusions: Serum FGF19 was suppressed and bile acid production up-regulated on conventional bile acid sequestrants, but not with A3384. This colonic-release formulation of colestyramine produced symptomatic benefit in patients with BAD.
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| 2. |
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| 3. |
- Bajor, Antal, 1962
(författare)
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Bile Acid Induced Diarrhoea Pathophysiological and Clinical Aspects
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A common cause for referral to gastroenterologists is chronic watery diarrhoea. Approximately 40% of these patients have idiopathic bile acid malabsorption (BAM) ? a condition with unknown aetiology. The 75SeHCAT test, which correlates inversely with faecal excretion and hepatic synthesis of bile acids, is used to diagnose BAM. The aims of the thesis were to study different mechanisms behind BAM. We investigated the stability of the 75SeHCAT test in diarrhoea patients having done the test twice, and in healthy controls. The 75SeHCAT values were stable over time, suggesting that in clinical practice there is no indication for a second test. There was also a strong negative correlation between the 75SeHCAT retention and the plasma marker for hepatic bile acid synthesis ?C4? both in diarrhoea and in controls. Impaired ileal absorption of bile acids may be secondary to a defective ileal reabsorbtion system. We assessed bile acid uptake in ileal biopsies from diarrhoea patients - both with normal and abnormal 75SeHCAT test- and compared with the bile acid uptake in ileal biopsies from patients with normal bowel habits. Our data suggest that BAM is not caused by impaired bile acid uptake in the ileum. We also tested whether BAM is associated with increased active small intestinal chloride secretion as estimated from small intestinal potential difference (PD) measurements. We recorded PD during manometry in patients with abnormal 75SeHCAT test and compared the values with PD recording values in healthy controls. There was a higher PD in the fasting state in the BAM group and there was also a negative correlation between the 75SeHCAT test values and the estimated chloride secretion. It is known that budosenide has effect on symptoms of diarrhoea both in Crohn?s disease and in collagenous colitis. We investigated whether the improvement in symptoms in collagenous colitis is associated with an enhancement of bile acid uptake and/or changes in bile acid synthesis. After 8 weeks of budesonide treatment the 75SeHCAT values increased significantly, synthesis rate decreased and the diarrhoea symptoms improved. Conclusions: The 75SeHCAT test is stable over a long period of time. C4, the plasma marker for bile acid synthesis, may be used in clinical practice instead of the 75SeHCAT test. BAM does not seem to be caused by impaired absorption of bile acids in the ileum. A possible mechanism is increased small intestinal fluid secretion and motility, which in turn overrides the absorptive capacity of the colonic mucosa and leads to diarrhoea. The positive symptomatic effects of budesonide in collagenous colitis may in part be mediated by increased ileal absorption and lower colonic concentrations of bile acids.
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| 4. |
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| 5. |
- Bajor, Antal, 1962, et al.
(författare)
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Indirect evidence for increased mechanosensitivity of jejunal secretomotor neurones in patients with idiopathic bile acid malabsorption.
- 2009
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Ingår i: Acta physiologica (Oxford, England). - : Wiley. - 1748-1716 .- 1748-1708. ; 197:2, s. 129-37
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Tidskriftsartikel (refereegranskat)abstract
- The interdigestive motor rhythm, the migrating motor complex (MMC), is accompanied by active secretion of chloride during periods of distally propagating maximal motor activity (MMC phase III). We studied the behaviour of this system in bile acid malabsorption (BAM), a relative common cause of chronic diarrhoea. We measured motor activity and transmucosal potential difference (PD, reflecting active chloride secretion), in the proximal jejunum in healthy controls (n = 18) and in a group of patients with BAM (n = 11). The phase III-generated voltage was related to the degree of BAM quantified by the (75)SeHCAT test.
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| 6. |
- Bajor, Antal, 1962, et al.
(författare)
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Normal or increased bile acid uptake in isolated mucosa from patients with bile acid malabsorption.
- 2006
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Ingår i: Eur J Gastroenterol Hepatol. - 0954-691X. ; 18:4, s. 397-403
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Bile acid malabsorption as reflected by an abnormal 75Se-labelled homocholic acid-taurine (75SeHCAT) test is associated with diarrhoea, but the mechanisms and cause-and-effect relations are unclear. Objectives: Primarily, to determine whether there is a reduced active bile acid uptake in the terminal ileum in patients with bile acid malabsorption. Secondarily, to study the linkage between bile acid malabsorption and hepatic bile acid synthesis. Methods: Ileal biopsies were taken from patients with diarrhoea and from controls with normal bowel habits. Maximal active bile acid uptake was assessed in ileal biopsies using a previously validated technique based on uptake of 14C-labelled taurocholate. To monitor the hepatic synthesis, 7[alpha]-hydroxy-4-cholesten-3-one, a bile acid precursor, was assayed in blood. The 75SeHCAT-retention test was used to diagnose bile acid malabsorption. Results: The taurocholate uptake in specimens from diarrhoea patients was higher compared with the controls [median, 7.7 (n=53) vs 6.1 [mu]mol/g per min (n=17)] (P<0.01) but no difference was seen between those with bile acid malabsorption (n=18) versus diarrhoea with a normal 75SeHCAT test (n=23). The 75SeHCAT values and 7[alpha]-hydroxy-4-cholesten-3-one were inversely correlated. Conclusions: The data do not support bile acid malabsorption being due to a reduced active bile acid uptake capacity in the terminal ileum. (C) 2006 Lippincott Williams & Wilkins, Inc.
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| 7. |
- Bajor, Antal, 1962, et al.
(författare)
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The bile acid turnover rate assessed with the (75)SeHCAT test is stable in chronic diarrhoea but slightly decreased in healthy subjects after a long period of time.
- 2008
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Ingår i: Digestive diseases and sciences. - : Springer Science and Business Media LLC. - 0163-2116 .- 1573-2568. ; 53:11, s. 2935-40
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Tidskriftsartikel (refereegranskat)abstract
- The stability of bile acid turnover rate was evaluated retrospectively using repeat SeHCAT tests in patients with chronic diarrhoea and prospectively for 16 years in healthy subjects. The SeHCAT values were stable in 39 patients with chronic diarrhoea, as shown by a comparison of the test results [data presented as median and (25th-75th percentile)]: 18% (8-23) in the first test versus 14% (9-21) in the second test [n = 39, P = 0.37, time interval 44 months (16-68), repeatability index >95%]. In contrast, they were reduced after 16 years in healthy subjects: 38% (30-49.5) in the first test versus 31% (21-49.5) in the second test (P < 0.03). In healthy subjects, the body mass index increased by 13% from 23.2 kg/m(2) (21-24.6) to 26.2 kg/m(2) (22.5-27.8) (P < 0.01) during the 16 years. There was a negative correlation between hepatic bile acid synthesis and the SeHCAT values (r = -0.615, P = 0.02, n = 14). In conclusion, the turnover rate of bile acids is stable over a long period of time in patients with chronic diarrhoea irrespective of bile acid malabsorption, suggesting that a repeat SeHCAT test is dispensable. There is a significant negative correlation between bile acid synthesis and SeHCAT test results in healthy subjects. The SeHCAT test values are slightly reduced in healthy subjects after 16 years.
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| 8. |
- Dahlén, Rahil, et al.
(författare)
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Global mucosal and serum cytokine profile in patients with ulcerative colitis undergoing anti-TNF therapy
- 2015
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 50:9, s. 1118-1126
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective. The knowledge of the effects of anti-tumour necrosis factor (TNF) treatment on the global cytokine profile in patients with ulcerative colitis (UC) is limited. A better understanding of these mechanisms could improve the ability to select patients that should undergo the therapy. Therefore, the aim was to determine the global mucosal and serum cytokine profile before and during induction therapy with anti-TNF in UC patients. Materials and methods. In total, mucosal biopsies (n = 28) and serum samples (n = 42) were collected from UC patients (total n = 48) before anti-TNF therapy. At week 14 response to the therapy was evaluated and again mucosal biopsies (n = 14) and serum samples (n = 42) were collected. Quantitative real-time PCR was used to determine mucosal cytokine mRNA expression and the MSD MULTI-ARRAY assay system platform was used for analysis of cytokines in serum. The global cytokine profile was evaluated by multivariate factor analysis. Results. At baseline, the global profile of mucosal cytokine mRNA expression and serum cytokines discriminated therapy responders from non-responders. Responders had lower mucosal mRNA expression of interleukin 1 beta (IL-1 beta), IL-17A, IL-6 and interferon gamma (IFN-gamma) than non-responders. Fourteen weeks after therapy start mucosal IL-1 beta and IL-6 were down-regulated in therapy responders but not in non-responders. At week 14, serum levels of IL-6 were decreased in therapy responders whereas IFN-gamma and IL-12p70 were increased in non-responders. Conclusions. Our data suggest that patients with a therapy failure have a more severe pro-inflammatory cytokine profile before start of anti-TNF treatment, which is less well suppressed by the treatment as compared to therapy responders.
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| 9. |
- Johannesson, Elisabet, et al.
(författare)
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Physical activity improves symptoms in irritable bowel syndrome: a randomized controlled trial.
- 2011
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Ingår i: The American journal of gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 1572-0241 .- 0002-9270. ; 106:5, s. 915-22
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity has been shown to be effective in the treatment of conditions, such as fibromyalgia and depression. Although these conditions are associated with irritable bowel syndrome (IBS), no study has assessed the effect of physical activity on gastrointestinal (GI) symptoms in IBS. The aim was to study the effect of physical activity on symptoms in IBS.
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| 10. |
- Krarup, Anne L., et al.
(författare)
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Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain.
- 2011
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Ingår i: Alimentary pharmacology & therapeutics. - : Wiley. - 1365-2036 .- 0269-2813. ; 33:10, s. 1113-22
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Tidskriftsartikel (refereegranskat)abstract
- Background Many patients with gastro-oesophageal reflux disease (GERD) are hypersensitive to heat and acid and may respond insufficiently to standard treatment. Antagonists of the heat and acid receptor ‘transient receptor potential vanilloid 1’(TRPV1) are a potential drug class for GERD treatment. Aim To investigate the effect of a TRPV1 antagonist (AZD1386) on experimentally induced oesophageal pain. Methods Twenty-two healthy men (20–31 years) participated in this randomised, placebo-controlled, double-blinded, crossover study examining the effects of a single-dose oral AZD1386 (30 and 95 mg). Subjects were block-randomised. On treatment days, participants were stimulated with painful heat, distension, electrical current and acid in the oesophagus. Heat and pressure pain on the forearm were somatic control stimuli. Data analysis: intention-to-treat. Results A total of 21 participants completed the protocol and 1 voluntarily discontinued. In the oesophagus, both 30 and 95 mg of AZD1386 increased pain thresholds to heat stimuli 23% [95% confidence interval (CI): 10–38%] and 28%, respectively (CI: 14–43%). The skin heat tolerance was increased 2.1 °C (CI: 1.1–3.2 °C) after 30 mg AZD1386 and 4.0 °C (CI: 3.0–5.0 °C) after 95 mg. Heat analgesia persisted for 2.5 h. Pain thresholds to the other stimuli were unaffected by AZD1386. 50% reported ‘feeling cold’ and body temperature increased in all subjects exposed to 30 and 95 mg AZD1386 (mean increase 0.4 ± 0.3 °C and 0.7 ± 0.3 °C, respectively, P < 0.05). Conclusions AZD1386 increased oesophageal and skin heat pain thresholds and had a safe adverse-event profile. This drug class may have a potential for treatment of GERD (ClinicalTrials.gov identifier: NCT00711048).
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| 11. |
- Magnusson, Maria K, 1972, et al.
(författare)
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Anti-TNF Therapy Response in Patients with Ulcerative Colitis Is Associated with Colonic Antimicrobial Peptide Expression and Microbiota Composition
- 2016
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 10:8, s. 943-952
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Anti-tumour necrosis factor [TNF] therapy is used in patients with ulcerative colitis [UC], but not all patients respond to treatment. Antimicrobial peptides [AMPs] and the gut microbiota are essential for gut homeostasis and may be important for treatment outcome. The aim of this study was to determine AMP and microbiota profiles in patients with UC before anti-TNF therapy start and correlate these data to treatment outcome.METHODS: Serum and biopsies were obtained from UC patients naïve to biological therapy [n = 56] before anti-TNF therapy start [baseline]. Fecal samples were taken at baseline and Weeks 2 and 6. Quantitative proteomic analysis was performed in mucosal biopsies. Expression of AMPs and cytokines was determined in biopsies and serum. Microbiota analysis of fecal samples was performed using GA-map™ Dysbiosis Test and real-time quantitative polymerase chain reaction [rtPCR]. Treatment response was evaluated 12-14 weeks after baseline.RESULTS: At baseline, proteomic analysis of biopsies showed that treatment responders and non-responders had differential expression of AMPs. Eleven AMP and AMP-related genes were analysed by rtPCR in mucosal biopsies and could together discriminate responders from non-responders at baseline. The most important nominators for response were increased expression of defensin 5 and eosinophilic cationic protein. Microbiota analysis revealed lower dysbiosis indexes and higher abundance of Faecalibacterium prausnitzii in responders compared with non-responders at baseline. Also, abundance of F. prausnitzii increased during induction therapy in responders.CONCLUSIONS: Anti-TNF therapy responders and non-responders display distinctly separate patterns of mucosal AMP expression and gut microbiota before treatment start. This indicates that intestinal antimicrobial/microbial composition can influence treatment outcome.
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| 12. |
- Magnusson, Maria K, 1972, et al.
(författare)
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CD25 and TNF receptor II reflect early primary response to infliximab therapy in patients with ulcerative colitis
- 2013
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Ingår i: United European Gastroenterology Journal. - : Wiley. - 2050-6406 .- 2050-6414. ; 1:6, s. 467-476
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Tidskriftsartikel (refereegranskat)abstract
- Background Although infliximab treatment is an option for patients with ulcerative colitis (UC), not all patients do respond to therapy, and cellular mechanisms leading to therapy response are incompletely known. Objective The objective of this article is to determine early effects of infliximab therapy on T cells in the blood of UC patients and if effects differed in therapy responders and nonresponders. Methods: Blood samples were obtained before and two weeks post-treatment start from 34 anti-tumor necrosis factor (TNF) therapy-naïve UC patients undergoing infliximab therapy. Response to therapy was evaluated prior to the fourth treatment dose. Expression of T cell surface markers and levels of soluble receptors and cytokines in serum were determined. Results At baseline, there were no differences in cellular, biochemical or clinical parameters between therapy responders and nonresponders. Infliximab therapy reduced frequencies of CD25+ T cells and increased frequencies of annexin V+ T cells in patients responding to infliximab, but not in nonresponding patients, two weeks after therapy start. Only therapy responders had decreased serum levels of sCD25 and sTNFRII two weeks after treatment start. In contrast, clinical parameters did not reflect therapy outcome already two weeks after therapy start. Conclusion Soluble and membrane-bound T cell receptors may be early indicators of infliximab therapy response in UC, which can be of clinical importance for the decision when to continue or to stop the treatment.
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| 13. |
- Magnusson, Maria K, 1972, et al.
(författare)
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Cultured blood T-cell responses predict anti-TNF therapy response in patients with ulcerative colitis
- 2015
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Ingår i: Alimentary Pharmacology & Therapeutics. - : Wiley. - 0269-2813. ; 41:11, s. 1149-1161
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAnti-tumour necrosis factor (TNF) therapy is used for treatment of ulcerative colitis (UC). As approximately 30% of patients with UC do not benefit from the treatment, it is of clinical interest to identify biomarkers of response before therapy is initiated. AimTo identify prognostic biomarkers of anti-TNF therapy response in anti-TNF therapy-naive patients with UC. MethodsPeripheral blood cells were obtained from 56 patients with UC before therapy started. Thirty-four patients were included in an exploratory cohort and 22 patients in a validation cohort. Blood cells were stimulated in vitro with influenza vaccine with and without anti-TNF. T-cell surface receptor expression and cytokine release were determined (in total 17 variables). Treatment response was evaluated using the Mayo score 12-14weeks after the first infusion. ResultsIn the exploratory cohort, blood cells from the patients showed stronger anti-TNF-dependent suppression of T-cell surface receptor expression and cytokine secretion among therapy responders than nonresponders. In particular, anti-TNF suppressed the expression of CD25 on T cells and secretion of interleukin 5, to a higher degree in responders than in nonresponders. These variables were used to a create model to predict therapy outcome, which was confirmed in the validation cohort. Correct classification of future therapy response was achieved in 91% of the cases in the validation cohort. ConclusionThe effects of anti-TNF on cultured blood T cells, obtained before therapy started, predict treatment outcome in patients with UC.
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| 14. |
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| 15. |
- Mottacki, Nima, et al.
(författare)
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Review article: bile acid diarrhoea - pathogenesis, diagnosis and management.
- 2016
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Ingår i: Alimentary pharmacology & therapeutics. - : Wiley. - 1365-2036 .- 0269-2813. ; 43:8, s. 884-898
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Forskningsöversikt (refereegranskat)abstract
- Bile acid diarrhoea results from imbalances in the homoeostasis of bile acids in the enterohepatic circulation. It can be a consequence of ileal disease/dysfunction, associated with other GI pathology or can be idiopathic.
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| 16. |
- Simrén, Magnus, 1966, et al.
(författare)
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Fecal incontinence in irritable bowel syndrome: Prevalence and associated factors in Swedish and American patients
- 2017
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925. ; 29:2
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundFecal incontinence (FI) is a prevalent but poorly recognized problem in the general population with profound negative effects on daily life. The prevalence of FI in irritable bowel syndrome (IBS) and its association with clinical, demographic, and pathophysiological factors remain largely unknown. MethodsOne US (n=304) and one Swedish (n=168) patient cohort fulfilling Rome III criteria for IBS completed Rome III diagnostic questions on FI and IBS symptoms, and questionnaires on IBS symptom severity, quality of life, anxiety and depression, and work productivity impairment. The patients also underwent assessments of colorectal sensitivity and motility. Key ResultsFecal incontinence one day per month was reported by 19.7% (USA) and 13.7% (Sweden) of IBS patients. These proportions rose to 43.4% and 29.8% if patients with less frequent FI were included. Fecal incontinence prevalence was higher in older age groups, with a clear increase above age 40. Irritable bowel syndrome patients with FI reported greater overall IBS symptom severity, more frequent and loose stools, and greater urgency. Negative effects of FI on quality of life, psychological distress, and work productivity were demonstrated. No associations were found between colorectal physiology and FI. Conclusions & InferencesFecal incontinence is common in IBS patients, and similar to previous general population reports, the major risk factors for FI in IBS are older age, rectal urgency, and loose, frequent stools. When IBS patients have comorbid FI, the impact on quality of life, psychological symptoms, and work impairment appears greater.
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