Morbidity, risk of cancer and mortality in 3645 HFE mutations carriers.

BACKGROUND & AIMS: Mutations in the HFE gene can lead to hereditary haemochromatosis (HH) and have been suggested to increase the risk of extra-hepatic diseases, especially breast and colorectal cancer. Here we investigated long-term outcomes of Swedish patients with HFE mutations. METHODS: We identified 3645 patients with a homozygous p.C282Y (62%) or a compound heterozygous p.C282Y/p.H63D (38%) mutation from eight centres in Sweden between 1997 and 2017. These were matched 1:10 by age, sex and county of residence to reference individuals from the general population. We ascertained incident outcomes until the end of 2017 by linkage to national registers. Studied outcomes were HH, cirrhosis, hepatocellular carcinoma (HCC), breast cancer (in women), colorectal cancer, type 1 and 2 diabetes, hypothyroidism, Parkinson's disease and mortality. Cox proportional hazards regression was used to estimate hazard ratios for these outcomes. RESULTS: Median age at diagnosis was 52 years, 44% were females. During a mean follow-up of 7.9 years, we found an increased risk for HCC, HH, cirrhosis, type 2 diabetes, osteoarthritis and death. Excess mortality was only seen in men. No increased risk was seen for colorectal or breast cancer. Liver-related outcomes were rare, with a cumulative incidence of <1%. CONCLUSIONS: Individuals found to be HFE mutation carriers in a university hospital setting had an increased risk for mortality in men, along with increased risks of cirrhosis, HCC, diabetes type 2, and osteoarthritis. In general, the absolute risk for adverse outcomes was low and no increased risk for colon or breast cancer was observed.

Symptom pattern following a meal challenge test in patients with irritable bowel syndrome and healthy controls.

BACKGROUND: Patients with irritable bowel syndrome (IBS) often complain of worsening of symptoms after meal intake. Meal challenge tests have previously been used to study symptoms and pathophysiology in functional dyspepsia. OBJECTIVE: The objective of this article is to evaluate differences in gastrointestinal (GI) symptom response to a standardized meal test in IBS compared to healthy controls. METHODS: We included 67 patients with IBS and 16 healthy controls. After an overnight fast the subjects were served breakfast (540 kcal; 36% fat, 15% proteins, 49% carbohydrates; 8.9 g fiber). They completed visual analog scales assessing severity of six GI symptoms (abdominal pain, bloating, discomfort, nausea, gas, fullness) before breakfast and every 30 minutes up to 240 minutes after breakfast. The patients also completed a questionnaire (IBS-SSS) to assess IBS symptom severity during the preceding week. The course of symptom scores over time was analyzed using mixed models. RESULTS: The meal was well tolerated and all subjects completed the test period. In patients, significant effects of time (initial increase to a maximum, followed by a return to baseline) were found for fullness, bloating, nausea and discomfort (all p values < 0.01 for linear, quadratic and third-order effect of time). In IBS patients, an independent significant association between IBS-SSS scores and all postprandial symptoms, except for nausea, was found (all p < 0.01). In controls, a significant linear, quadratic and third-order effect of time (all p < 0.0001) was found for fullness only. The difference in time course for bloating and discomfort between IBS patients and controls was confirmed when comparing the groups directly (significant time-by-group interaction effects, all p < 0.05), but not for nausea. On average, IBS patients scored significantly higher than controls on all symptoms, except for nausea (significant main effects of group, all p < 0.05). CONCLUSIONS: A standardized meal test seems to be a promising tool to study the symptom pattern in IBS and potentially to follow the effect of interventions.

Increased TLR2 expression on blood monocytes in irritable bowel syndrome patients.

OBJECTIVES: The understanding of the mechanisms for increased immune activation in subgroups of patients with irritable bowel syndrome (IBS) is incomplete. We hypothesized that monocytes are more activated in patients with IBS than in the healthy population. We therefore examined activation phenotype and cytokine secretion of blood monocytes. METHODS: Blood samples from 74 patients with IBS and 30 controls were obtained. The activation phenotype of CD11cCD14 monocytes and cytokine secretion in serum and in peripheral blood mononuclear cells cultured with or without lipopolysaccharide was determined. Gastrointestinal and psychological symptom severity and quality of life were assessed using validated questionnaires. RESULTS: Monocytes from patients demonstrated an increased expression of toll-like receptor (TLR) 2, whereas the expression on monocytes of TLR4, HLA-DR, CD40, CD80 and CD86 was comparable in patients and controls. The expression of activation markers on monocytes did not correlate with gastrointestinal or extracolonic symptom severity, but the expressions of TLR2, HLA-DR and CD86 were associated with less severe psychological symptoms and better social and physical well-being. Cytokine secretion in serum and peripheral blood mononuclear cell cultures was comparable in patients and controls. A subgroup of patients (15%) who had TLR2 and HLA-DR expression intensity above the level seen in controls reported less severe psychosocial symptoms. CONCLUSION: Patients with IBS have increased expression of TLR2 on monocytes and the activation level on monocytes correlates with less severe psychological symptoms and better quality of life. Thus, our data implicate less importance of psychosocial factors and increased importance of immunological parameters for symptom generation in a subgroup of patients with IBS.

Structured patient education is superior to written information in the management of patients with irritable bowel syndrome: a randomized controlled study.

OBJECTIVE: Education and reassurance are proposed to be of great importance in the management of patients with irritable bowel syndrome (IBS), but few trials supporting this are available. Our aim was to compare the effects of a structured patient group education (IBS school) versus receiving written information in the form of an IBS guidebook, on knowledge, symptoms, and quality of life in IBS patients. METHODS: Patients with IBS according to the Rome II criteria were randomized to participate in the group education or to receive the guidebook. The effects were evaluated by self-administered questionnaires at 3 and 6 months after baseline. RESULTS: One hundred and forty-three patients - 71 in the guidebook group and 72 in the IBS school group - completed the study. Compared with the guidebook group, the patients in the education group showed greater reduction in IBS symptom severity and gastrointestinal (GI)-specific anxiety, as well as greater improvement in perceived knowledge of IBS. Several aspects of health-related quality of life were significantly improved after the group education, but not in the group who received the written information. CONCLUSION: A structured patient group education is superior to written information to enhance knowledge of IBS, and improve GI symptoms and GI-specific anxiety in IBS patients.

T-cell activation in patients with irritable bowel syndrome.

OBJECTIVES: Irritable bowel syndrome (IBS) has been found to be associated with low-grade immune activation in a subset of patients. We therefore investigated blood and colonic T-cell activity in IBS patients. METHODS: Blood samples were initially obtained from 74 IBS patients and 30 controls. Supplementary blood samples, to confirm data, were taken from another cohort (26 patients and 14 controls). In addition, colonic biopsies were taken from a third cohort (11 patients and 10 controls). Peripheral blood and colonic mononuclear cells were stimulated with anti-CD3/CD28 antibodies. Proliferation, cytokine secretion, and T-cell phenotype were investigated. IBS symptom severity was assessed. RESULTS: IBS patients displayed an activated phenotype with increased frequencies of blood T cells expressing CD69 and integrin beta7/HLA-DR. Anti-CD3/CD28-stimulated blood and colonic T cells from IBS patients proliferated less than T cells from controls. IBS patients had an increased polyclonally stimulated T-cell secretion of IL-1beta, which also weakly correlated with increased bowel habit dissatisfaction. Furthermore, despite normal frequencies of CD25high T cells in the blood of IBS patients, lower blood CD25high T-cell frequencies were modestly correlated with more bowel habit dissatisfaction and increased total IBS symptom severity. CONCLUSIONS: IBS patients have an increased frequency of activated T cells, demonstrated by the expression of activation markers and reduced proliferation in response to restimulation in vitro. The increased level of T-cell activation is consistent with the hypothesis of low-grade immune activation in IBS and may also be involved in symptom generation in IBS.

Hypervigilance in irritable bowel syndrome compared with organic gastrointestinal disease.

OBJECTIVE: Irritable bowel syndrome (IBS) patients are suggested to selectively attend to gastrointestinal (GI) sensations compared with healthy controls. However, it remains unclear whether there are differences between IBS and other chronic GI disorders. We aimed to evaluate the presence of hypervigilance towards the GI tract in IBS compared with patients with organic GI diseases. METHODS: We included 36 IBS patients and 40 age- and gender-matched patients with organic GI disease. They completed the Hospital Anxiety and Depression Scale (HADS) and underwent three tests: (1) word association-write down as many words as possible representing signs of disease; (2) word recognition (tachistoscope)-four categories of words (positive affects, non-GI symptoms, GI symptoms, negative affects) displayed for increasing time until identified; (3) word recollection-memorize words (10 GI symptoms, 10 positive affects, 10 negative affects). RESULTS: The word-association task did not show group differences. IBS patients were significantly faster than organic GI patients at recognizing words representing GI symptoms (21 vs. 26 ms; P=.04) and negative affects (27 vs. 34 ms; P=.03), but also tended to be faster at recognizing positive affects (24 vs. 29 ms; P=.08) and non-GI symptoms (22 vs. 27 ms; P=.2). Both groups remembered a similar number of words, but IBS patients tended to recall more incorrect GI words than organic patients (1.3 vs. 1.0; P=.06). There were no group differences in HADS scores. CONCLUSION: Compared to patients with organic GI disease, IBS patients seem to be hypervigilant for information regarding GI sensations and maybe also negative information.

Altered rectal perception in irritable bowel syndrome is associated with symptom severity.

BACKGROUND & AIMS: Diverging results exist regarding the connection between altered visceral perception and gastrointestinal (GI) symptoms, as well as the effects of psychological status on visceral sensitivity. We sought to investigate different aspects of rectal perception in irritable bowel syndrome (IBS) and the association with GI and psychological symptoms. METHODS: We included 109 patients with IBS meeting Rome II criteria (77 women; age range, 20-71 years) and 29 healthy controls (21 women; age range, 20-68 years). They underwent rectal balloon distentions determining sensory thresholds for discomfort and pain, the perceived intensity of unpleasantness, and the viscerosomatic referral area. The fifth percentile (thresholds) and 95th percentile (unpleasantness and referral area) in controls were used to define altered perception. Questionnaires were used to assess severity of IBS-related GI symptoms and psychological symptoms. RESULTS: When combining the 3 aspects of perception, 67 patients (61%) had altered rectal perception. These patients, compared with normosensitive patients, more frequently reported moderate or severe pain (73% vs 44%; P < .01), bloating (73% vs 36%; P < .0001), diarrhea (47% vs 21%; P < .01), satiety (39% vs 13%; P < .01), and clinically significant anxiety (31% vs 12%; P < .05). In a multivariate analysis, only pain and bloating remained associated with altered rectal perception. CONCLUSIONS: Altered rectal perception is common in IBS and seems to be one important pathophysiologic factor associated with GI symptom severity in general and pain and bloating in particular. It is not just a reflection of the psychological state of the patient.

Small intestinal bacterial overgrowth in patients with irritable bowel syndrome.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) has been proposed to be common in irritable bowel syndrome (IBS), with altered small-bowel motility as a possible predisposing factor. AIM: To assess the prevalence of SIBO, by culture of small-bowel aspirate, and its correlation to symptoms and motility in IBS. METHODS: 162 patients with IBS who underwent small-bowel manometry and culture of jejunal aspirate were included. Cultures from 26 healthy subjects served as controls. Two definitions of altered flora were used: the standard definition of SIBO (>/=10(5) colonic bacteria/ml), and mildly increased counts of small-bowel bacteria (>/=95th centile in controls). RESULTS: SIBO (as per standard definition) was found in 4% of both patients and controls. Signs of enteric dysmotility were seen in 86% of patients with SIBO and in 39% of patients without SIBO (p = 0.02). Patients with SIBO had fewer phase III activities (activity fronts) than patients without SIBO (p = 0.08), but otherwise no differences in motility parameters were seen. Mildly increased bacterial counts (>/=5x10(3)/ml) were more common in patients with IBS than in controls (43% vs 12%; p = 0.002), but this was unrelated to small intestinal motility. No correlation between bacterial alterations and symptom pattern was observed. CONCLUSIONS: The data do not support an important role for SIBO according to commonly used clinical definitions, in IBS. However, mildly increased counts of small-bowel bacteria seem to be more common in IBS, and needs further investigation. Motility alterations could not reliably predict altered small-bowel bacterial flora.

Functional findings in irritable bowel syndrome.

The pathophysiology of IBS is complex and still incompletely known. Both central and peripheral factors, including psychosocial factors, abnormal GI motility and secretion, and visceral hypersensitivity, are thought to contribute to the symptoms of IBS. Several studies have demonstrated altered GI motor function in IBS patients and the pattern differs between IBS subgroups based on the predominant bowel pattern. Few studies have so far addressed GI secretion in IBS, but there are some evidence supporting altered secretion in the small intestine of IBS patients. Visceral hypersensitivity is currently considered to be perhaps the most important pathophysiological factor in IBS. Importantly, several external and internal factors can modulate visceral sensitivity, as well as GI motility, and enhanced responsiveness within the GI tract to for instance stress and nutrients has been demonstrated in IBS patients. Today IBS is viewed upon as a disorder of dysregulation of the so-called brain-gut axis, involving abnormal function in the enteric, autonomic and/or central nervous systems, with peripheral alterations probably dominating in some patients and disturbed central processing of signals from the periphery in others.

Health-related quality of life in patients attending a gastroenterology outpatient clinic: functional disorders versus organic diseases.

BACKGROUND & AIMS: Several gastrointestinal (GI) disorders have major effects on health-related quality of life (HRQOL), but there are few direct comparisons between functional GI disorders and organic GI diseases. This study aimed to compare HRQOL between these 2 groups and to assess factors of importance for HRQOL. METHODS: Three hundred ninety-nine consecutive patients attending a GI outpatient clinic completed HRQOL instruments (Short Form 36 [SF-36] and Psychological General Well-Being index [PGWB]) and the Gastrointestinal Symptom Rating Scale (GSRS). For the analyses we divided the patients into 2 diagnostic groups: functional GI disorders (n = 112) and organic GI diseases (n = 287). RESULTS: Compared with norm values on SF-36 and PGWB, both patient groups exhibited profound reductions in HRQOL. After correcting for age, gender, and disease duration, patients with a functional GI disorder had significantly lower scores than patients with an organic GI disease on 6 of 8 SF-36 domains and 5 of 6 PGWB domains. Vitality and anxiety on PGWB, abdominal pain and diarrhea on GSRS, age, and gender independently contributed to the physical component score of SF-36 (adjusted R(2) = 32%). Patients with a functional GI disorder had more severe reflux, abdominal pain, constipation, and indigestion, but the severity of diarrhea did not differ between the groups. HRQOL was reduced with increasing severity of GI symptoms. CONCLUSION: GI disorders have profound effects on HRQOL, and the impact is greater in patients with functional GI disorders as compared with organic GI diseases. The reduction in HRQOL is associated with the severity of both psychological and GI symptoms.