Celiac disease and risk of neuropsychiatric disorders: A nationwide cohort study.

INTRODUCTION: Previous studies have indicated that patients with celiac disease (CD) may have an increased risk of developing neuropsychiatric disorders. However, large-scale epidemiologic studies on the topic are still scarce. We aimed to examine the association between CD and development of neuropsychiatric disorders during an 18-year follow-up period. METHODS: We conducted a prospective cohort study. All Danish patients with an incident diagnosis of CD (ICD-10 K90.0) from 2000 to 2018 were identified in nationwide registries and compared with birthdate- and sex-matched controls (variable 1:10 ratio) for the development of a neuropsychiatric disease. Individual neuropsychiatric diseases were also examined. The absolute risk was calculated by the cumulative incidence, and the relative risk was estimated in Cox regression models. RESULTS: We identified a cohort of 6329 patients with CD diagnosed from 2000 to 2018 and 63,287 matches at risk for developing incident neuropsychiatric disorders. The cumulative incidence of development of any neuropsychiatric disorder was 3.9%, 14.9%, 24.8%, 35.9% after 1, 5, 10, and 15 years of follow-up, respectively, in patients with CD compared with 1.8%, 9.3%, 18.3%, and 27.0% in controls. Gray's test for equality p < 0.001. The relative risk was HR = 1.58 (95% confidence interval: 1.49-1.68) in CD patients compared with matches. For the individual outcomes, CD was associated with an increased relative risk of developing anxiety, depression, eating disorders, epilepsy, migraine, and stress. We also found indications of an increased relative risk of ADHD, alcoholism, bipolar disorders, and drug abuse, although the associations were less clear. No associations were found between CD and dementia, Parkinson's disease, and schizophrenia. CONCLUSIONS: In this nationwide study including more than 6000 patients with CD, we found an increased risk of development of a neuropsychiatric disorder compared with age- and sex-matched controls. The causes and the clinical relevance of these associations remain to be elucidated.

Biochemical abnormalities among patients referred for celiac disease antibody blood testing in a primary health care setting.

To investigate possible biochemical abnormalities associated with celiac disease (CD) antibody positivity in a primary health care setting and thereby identify predictors that could potentially reduce diagnostic delay and underdiagnosis of CD. This observational cohort study included measurements of CD antibodies in the Copenhagen Primary Care Laboratory (CopLab) database from 2000 to 2015; CD antibody positivity was defined as tissue transglutaminase antibody IgA or IgG ≥ 7 kU/L and/or deamidated gliadin peptide antibody IgG ≥ 10 kU/L. Individuals with a prior diagnosis of CD were excluded. We examined differences between individuals with positive and negative CD antibody tests regarding the results of biochemical tests performed six months before and one month after the date of the CD antibody test. We identified 76,265 measurements of CD antibodies during 2000-2015, and 57,061 individuals met the inclusion criteria (706 antibody-positive and 56,355 antibody-negative). We found lower ferritin, hemoglobin, cobalamin and folic acid levels and higher levels of transferrin, ALAT (alanine transaminase), and alkaline phosphate among individuals with a positive CD antibody test. Furthermore, we illustrated more measurements below the sex-specific reference intervals for hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), ferritin, cobalamin and folic acid among individuals with a positive CD antibody test. This study identified several biochemical abnormalities associated with CD antibody positivity among individuals referred to CD antibody testing. The pattern of abnormalities suggested that micronutrient deficiencies were prevalent among CD antibody-positive individuals, confirming malabsorption as a sign of CD. These findings illustrate the possibility of reducing diagnostic delay and underdiagnosis of CD.

Diagnostic Delay in Coeliac Disease: A Survey among Danish Patients.

Background: Coeliac disease affects around 1% of the population, although many cases remain undiagnosed. Underdiagnosis and diagnostic delay in coeliac disease may cause health complications and be a burden for both the patient and society. Casuistic reports indicate that the diagnostic delay may be significant in Danish patients. Aim: To investigate the diagnostic delay among Danish patients with coeliac disease. Methods: We performed a survey among coeliac disease patients to investigate the diagnostic delay. A web-based questionnaire was sent to all members of The Danish Coeliac Society. Results: The questionnaire was completed by 1,392 individuals with a diagnosis of coeliac disease (78.1% women; mean age: 42.8 years). The mean delay was 1.8 (SD 5.0) years from the first symptom to the first health care contact and 5.8 (SD 9.5) years from the first symptom to diagnosis; 18.6% of the participants reported a total diagnostic delay of more than 10 years. Among the patient-reported reasons for delay were misunderstandings, unspecific symptoms, and a lack of knowledge or focus on coeliac disease among the doctors. In total, 52.7% rated the time to diagnosis to have been "too long," and 20.1% were not satisfied with the diagnostic process. However, the majority were "to some extent" or "very" satisfied with the diagnostic process. Conclusion: We found evidence of a significant diagnostic delay among Danish patients with coeliac disease. This was primarily due to the delay from the time of first health care contact to the time of diagnosis. This study highlights the importance of raising awareness of coeliac disease among health care professionals.

Symptoms and biomarkers associated with undiagnosed celiac seropositivity.

BACKGROUND: Studies have indicated that underdiagnosis and diagnostic delay are common in celiac disease. Therefore, it is important to increase our knowledge of what symptoms and biomarkers could identify undiagnosed cases of celiac disease. METHODS: We screened for celiac disease antibodies in stored blood samples from 16,776 participants in eight population-based studies examined during 1976-2012. Undiagnosed celiac seropositivity was defined as celiac disease antibody positivity (IgG-deamidated gliadin peptide above 10.0 U/mL and/or IgA-tissue transglutaminase (TTG) or IgG-TTG above 7.0 U/mL) without a known diagnosis of celiac disease in the National Patient Register. In all studies general health symptoms were recorded by participant-completed questionnaire, including self-perceived health, tiredness, headache and gastrointestinal symptoms. Furthermore, blood samples were drawn for analyses of biomarkers e.g. hemoglobin, blood glucose, cholesterol, liver parameters and vitamins. The participants with undiagnosed celiac seropositivity were matched by sex, age and study with four controls among the celiac disease antibody negative participants. RESULTS: We excluded, five participants with known celiac disease, resulting in a population of 16,771 participants. In this population 1% (169/16,771) had undiagnosed celiac seropositivity. There were no statistically significant differences in symptoms between cases and controls. Undiagnosed celiac seropositivity was associated with low blood cholesterol (< 5 mmol/L) and low hemoglobin (< 7.3 mmol/L for women and < 8.3 mmol/L for men). CONCLUSION: In this general population study, undiagnosed cases of celiac seropositivity did not have more symptoms than controls, confirming the diagnostic difficulties of celiac disease and the low prognostic value of symptoms for a diagnosis of celiac disease. Furthermore, decreased levels of cholesterol and/or hemoglobin in the blood were associated with undiagnosed celiac seropositivity.

Long-term Consequences of Undiagnosed Celiac Seropositivity.

INTRODUCTION: Diagnosed celiac disease (CD) is associated with lymphoproliferative malignancy and gastrointestinal cancer, but little is known about the long-term consequences of undiagnosed CD. We aimed to investigate long-term consequences of undiagnosed CD for mortality and incidence of cancer and other chronic diseases. METHODS: We screened biobank serum samples for immunoglobulin (Ig) A and IgG tissue transglutaminase (TTG) and IgG deamidated gliadin peptide in a study of 8 population-based cohort studies comprising 16,776 participants examined during 1976-2012 and followed with >99% complete follow-up in Danish nationwide registries until December 31, 2017, regarding vital status and incidence of diseases. Undiagnosed CD was defined as antibody positivity (IgA-TTG or IgG-TTG ≥ 7 U/mL and/or IgG deamidated gliadin peptide ≥ 10 U/mL) in individuals without a diagnosis of CD recorded in the National Patient Register. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox regression analyses with age as the underlying time scale. RESULTS: The prevalence of undiagnosed CD was 1.0% with no statistically significant increase over time. Undiagnosed CD was associated with increased risk of cancer overall (HR, 1.57; 95% CI, 1.16-2.11), gastrointestinal cancer (HR, 2.33; 95% CI, 1.35-4.04), cancer of the uterus (HR, 3.95; 95% CI, 1.46-10.69), breast cancer (HR, 1.98; 95% CI, 1.02-3.82), head and neck cancer (HR, 3.12; 95% CI, 1.15-8.43), and cardiovascular disease (HR, 1.37; 95% CI, 1.01-1.85). We found no statistically significant association between undiagnosed CD and mortality (HR, 1.19; 95% CI, 0.87-1.61). DISCUSSION: Undiagnosed CD was associated with increased risk of cardiovascular disease and cancer suggesting that untreated CD has serious long-term health consequences not only affecting the gastrointestinal tract (see Visual Abstract, Supplementary Digital Content, http://links.lww.com/AJG/B566).

The association of celiac disease and allergic disease in a general adult population.

Background: The relationship between allergy and celiac disease (CD) is not clear. Objective: The objective of this article is to investigate the association of CD and CD antibody positivity with hay fever, asthma and immunoglobulin (Ig)E sensitization in a general adult population. Methods: A total of 2297 individuals were screened for CD antibodies and underwent allergy testing. CD antibody-positive participants were invited to undergo clinical evaluation including biopsies. Additionally, biobank blood samples from four population-based studies (6423, 973, 1718 and 1101 participants) with data on IgE sensitization to inhalant allergens were screened for CD antibodies. CD antibody-positive participants were screened for serum IgE against food allergens in three biobank studies. CD-antibody positivity was defined as IgA or IgG tissue transglutaminase ≥7 U/ml and/or IgG deamidated gliadin peptide ≥10 U/ml. Results: The nine participants (0.4%) diagnosed with CD had significantly higher prevalence of IgE sensitization to wheat and dust mites. The prevalence of CD antibody positivity was 0.8% (18/2297), and these participants had a significantly higher prevalence of IgE sensitization to food allergens (Fx5), egg, dust mites and mugwort. In the biobank studies, the prevalence of CD antibody positivity was 0.8% to 1.2%. One study showed a positive association between CD antibody positivity and IgE sensitization for dog, horse and food allergens. Conclusion: We found a possible association of CD and IgE sensitization to some food and inhalant allergens in the Health2006 study. In further studies, however, we could not consistently replicate these associations.

A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults.

Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres.

The distribution of HLA DQ2 and DQ8 haplotypes and their association with health indicators in a general Danish population.

BACKGROUND: Human leukocyte antigen (HLA) DQ2 and DQ8 are important risk factors for some autoimmune diseases such as celiac disease (CD), but their possible role in other diseases and health conditions is not fully explored. OBJECTIVES: The objective of this article is to examine the distribution of HLA DQ2 and HLA DQ8 in an adult general population, and their association with health indicators (diseases, symptoms and biomarkers). METHODS: In this cross-sectional, population-based study, 2293 individuals were screened for HLA DQ2 and DQ8; CD-associated alleles (DQA*0201*03*05/DQB*02*0301/0304*0302/0305) and DQB1*02 homozygosity were determined for screen-positive participants. The National Patient Registry provided diagnosis information. RESULTS: A total of 47.7% (1093/2293) individuals were positive for DQ2 and/or DQ8: 31.2% (716/2293) only DQ2, 11.9% (273/2293) only DQ8, 4.1% (93/2293) both DQ2 and DQ8. Among nine individuals diagnosed with CD, 89.9% (8/9) had DQ2.5cis, 22.2% (2/9) DQ8 and 22.2% (2/9) DQ2.2 (two both DQ2 and DQ8). HLA DQ2.5 was associated with higher thyroid-stimulating hormone levels, while DQ2/DQ8-positive participants had significantly lower prevalence of irritable bowel syndrome (IBS). DQ2/DQ8 were strongly associated with CD, but no other registry-based diagnoses. CONCLUSION: In this general Danish population, 47.7% were HLA DQ2/DQ8 positive and thus potentially at risk for CD. All individuals with CD were DQ2/DQ8 positive; the majority DQ2.5. Surprisingly, DQ2/DQ8-positivity was associated with lower IBS prevalence.

Plasma Alkylresorcinols Reflect Gluten Intake and Distinguish between Gluten-Rich and Gluten-Poor Diets in a Population at Risk of Metabolic Syndrome.

BACKGROUND: Many patients with celiac disease experience difficulties in adherence to a gluten-free diet. Methods for testing compliance to a gluten-free diet are costly and cumbersome. Thus, a simple biomarker of gluten intake is needed in a clinical setting and will be useful for epidemiologic studies investigating wider effects of gluten intake. OBJECTIVE: The aim was to evaluate plasma total alkylresorcinol concentrations as a measure of gluten intake. METHODS: In this randomized, controlled, crossover intervention study in 52 Danish adults with features of the metabolic syndrome, we compared 8 wk of a gluten-rich and gluten-poor diet separated by a washout period of ≥6 wk. We measured fasting plasma concentrations of alkylresorcinols to determine if they reflected differences in gluten intake as a secondary outcome of the original study. In addition, we investigated in 118 Danish adults the cross-sectional association between self-reported gluten intake and plasma alkylresorcinols in the same and a similar study at baseline. We used mixed-model ANCOVA for examining treatment effects, a classification tree to determine compliance to the gluten-poor diet, and linear regression models for examining baseline correlation between plasma alkylresorcinol concentrations and gluten intake. RESULTS: Plasma total alkylresorcinols decreased more during the gluten-poor period (geometric mean: -124.8 nmol/L; 95% CI: -156.5, -93.0 nmol/L) than in the gluten-rich period (geometric mean: -31.8 nmol/L; 95% CI: -63.1, -0.4 nmol/L) (P < 0.001). On the basis of the plasma alkylresorcinol profile, we built a classification tree to objectively determine compliance and found an overall participant misclassification error of 3.9%. In the cross-sectional study we found a 5.6% (95% CI: 2.4%, 8.9%) increase in plasma total alkylresorcinols per 1-g increase in reported gluten intake (P < 0.001). CONCLUSION: We propose the use of plasma alkylresorcinols to monitor compliance to a gluten-free diet as well as to help investigations into the possible effects of gluten in the wider population. This trial was registered at www.clinicaltrials.gov as NCT017119913 and NCT01731366.

Symptoms and biomarkers associated with celiac disease: evaluation of a population-based screening program in adults.

OBJECTIVES: To identify possible early predictors (symptoms and biomarkers) of celiac disease, compare symptoms before and after screening, and evaluate the diagnostic efficacy of serologic screening for celiac disease in an adult Danish population. METHODS: This cross-sectional population-based study was based on the 5-year follow-up of the Health2006 cohort, where 2297 individuals were screened for celiac disease; 56 were antibody positive and thus invited to clinical evaluation. Eight were diagnosed with biopsy-verified celiac disease. A follow-up questionnaire was sent to antibody-positive individuals 19 months after the clinical evaluation to obtain information on their symptoms and their experience with participation in the screening. RESULTS: Before screening, participants subsequently diagnosed with celiac disease did not differ from the rest of the population with respect to symptoms, but had significantly lower total cholesterol. Tissue transglutaminase IgA antibodies with a cut-off of 10 U/ml had a positive predictive value of 88%. The majority of participants were satisfied with their participation in the screening program. Individuals with celiac disease were generally satisfied with having been diagnosed and 71% felt better on a gluten-free diet. CONCLUSION: There were no differences in the prevalence of symptoms between participants with and without screening-detected celiac disease, confirming that risk stratification in a general population by symptoms is difficult. The majority of participants diagnosed with celiac disease felt better on a gluten-free diet despite not reporting abdominal symptoms before diagnosis and participants in the clinical evaluation were generally satisfied with participation in the screening program.

Screening for celiac disease in Danish adults.

OBJECTIVE: The prevalence of celiac disease (CD) as recorded in the Danish National Patient Registry is ∼50/100,000 persons. This is much lower than the reported prevalence of CD in other Nordic countries and underdiagnosis is suspected. Our aim was to estimate the prevalence of CD in a population-based study of Danish adults. METHODS: A total of 2297 adults aged 24-76 years living in the southwestern part of Copenhagen were screened for CD by immunoglobulin (Ig)A and IgG antibodies to transglutaminases and deamidated gliadin. IgA/IgG-positive participants were invited to a clinical evaluation, including biopsies, by a gastroenterologist. RESULTS: Of the invited 56 participants, 40 underwent a full clinical evaluation and 8 persons were diagnosed with CD; 2 of the 16 persons, who did not complete the clinical evaluation, were considered by experts to have probable CD. None of the above 56 participants had a known history of CD or a recorded diagnosis of CD in National Patient Registry. By combining cases of biopsy-proven CD (n = 8), probable CD (n = 2), and registry-recorded CD (n = 1), the prevalence of CD was estimated to be 479/100,000 (11/2297) persons (95% CI: 197-761). CONCLUSION: In this general adult population, the prevalence of CD as estimated by screening and clinical evaluation was 10 times higher than the registry-based prevalence of CD. Of 11 participants diagnosed with CD in our screening study, 10 were unaware of the diagnosis prior to the study. Thus, our study suggests that CD is markedly underdiagnosed in Danish adults.

Crohn's disease: ultrastructure of interstitial cells in colonic myenteric plexus.

The role of the interstitial cells of Cajal (ICC) in chronic inflammatory bowel disease, i.e., ulcerative colitis (UC) and Crohn's disease (CD), remains unclear. Ultrastructural alterations in ICC in the colonic myenteric plexus (ICC-MP) have been reported previously in UC, but descriptions of ICC-MP and other interstitial cells in the myenteric region of the colon are lacking for CD. In the present study, we characterized the ultrastructure of interstitial cells, nerves, and glial cells in the myenteric region in Crohn's colitis (CC). In comparison with controls, varicosities of the myenteric bundles were dilated and appeared to be empty. Lipid droplets and lipofuscin-bodies were prominent in glial cells and neurons. ICC-MP were scanty but, as in controls, had caveolae, prominent intermediate filaments, cytoplasmic dense bodies, and membrane-associated dense bands with a patchy basal lamina. ICC-MP were similar in the various colonic regions. ICC-MP in CC showed no signs of degeneration or cytological changes. As in controls, fibroblast-like cells had abundant coated vesicles but lacked prominent intermediate filaments and caveolae. Macrophages also appeared as in controls. In comparison with ICC-MP in UC, the cytology of ICC-MP in CC were thus undisturbed. The ultrastructural differences between UC and CC might reflect pathophysiological differences of importance for understanding pathogenetic differences between CD and UC.

A randomised double-blind placebo-controlled trial with Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp. lactis BB-12 for maintenance of remission in ulcerative colitis.

BACKGROUND AND AIMS: To investigate the clinical effect of treatment with Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp. lactis BB-12 (Probio-Tec AB-25) to maintain remission in patients with ulcerative colitis. METHODS: Patients with left-sided ulcerative colitis in remission - including proctitis and at least one relapse within the last year were randomised (2:1) in a double-blind placebo-controlled study to Probio-Tec AB-25 or placebo for 52 weeks. The patients were evaluated clinically, endoscopically and histologically at entry and if relapsing. No other medication for ulcerative colitis than the study drug was allowed during the study. Primary endpoint was maintenance of clinical remission, secondary endpoints comparisons of days to relapse, and safety and tolerability of the study drug. The concentrations of the probiotic bacterial strains in stool were analysed in a subset of patients. RESULTS: Thirty-two patients were randomised. Twenty patients received Probio-Tec AB-25 and twelve patients received placebo. Five patients (25%) in the Probio-Tec AB-25 group and one patient (8%) in the placebo group maintained remission after 1 year of treatment (p=0.37). The median time to relapse was 125.5days (range 11-391 days) in the probiotic group and 104 days (range 28-369 days) in the placebo group respectively, (p=0.683). Probio-Tec AB-25 was overall well tolerated. CONCLUSIONS: In this small randomised placebo-controlled trial no significant clinical benefit of Probio-Tec AB-25 could be demonstrated in comparison with placebo for maintaining remission in patients with left-sided ulcerative colitis. A difference may be achieved in larger studies, but the clinical significance of this would be questionable. This study was registered in ClinicalTrial.gov (NCT00268164).

Crohn's disease of the colon: ultrastructural changes in submuscular interstitial cells of Cajal.

Interstitial cells of Cajal (ICC) at the submuscular border of the human colon (ICC-SMP) are the proposed pacemaker cells of the musculature. In patients with Crohn's disease (CD) of the colon, ICC-SMP showed characteristic cytological changes from controls. The changes comprised secondary lysosomes in connection with lipid droplets and cytoplasmic vacuoles or multiple empty, confluent and often outbulging vacuoles merging with cisterns of granular endoplasmic reticulum and clusters of glycogen granules. These changes were most pronounced in patients with macroscopical mucosal inflammation but were also demonstrable in uninvolved colonic segments. Relationships of ICC to other cells were undisturbed. The changes were selective to ICC-SMP, as glial cells, muscle cells and fibroblast-like cells at the submuscular border showed no cytological alterations compared with controls. Varicosities of the submuscular plexus were often empty and dilated. Fibroblast-like cells selectively encased macrophages and mast cells. The cytological changes in ICC-SMP in CD are thus similar to changes seen in ulcerative colitis and may be of pathophysiological significance with regard to the motility and sensory disturbances seen in patients with CD.

Cyclooxygenase-2 immunoreactivity in collagenous colitis.

Collagenous colitis (CC) is an inflammatory bowel disease of unknown aetiology and pathogenesis. In ulcerative colitis and Crohn's disease, prostaglandins may be involved in the pathogenesis of inflammation, and increased expression of cyclo-oxygenase-2 (COX-2) has been detected. The purpose of this study was to examine the presence and cellular localization of COX-2 in colonic mucosa of patients with CC. Using immunohistochemistry, immunoflouresence and Western blot analysis, COX-2 expression was evaluated in colonic mucosal biopsies from 10 patients with active untreated CC, and compared with samples from eight normal controls, and samples from eight patients with ulcerative colitis or Crohn's disease. Specimens from patients with CC expressed COX-2 protein in increased amounts compared with controls, but similar to patients with ulcerative colitis and Crohn's disease. COX-2 expression was localized to the mononuclear cells of the lamina propria. COX-2 expression was most evident in macrophages. Co-localization of COX-2 and macrophages was increased in number in comparison with controls. In conclusion COX-2 is expressed in increased amounts primarily in the macrophage subpopulation of the inflammatory infiltrate of lamina propria in CC. Increased recruitment of macrophages, increased expression of COX-2 and increased prostaglandin synthesis may be involved in the pathogenesis of CC.

Ultrastructure of Cajal-like interstitial cells in the human detrusor.

The aim of this ultrastructural study was to examine the human detrusor for interstitial cells of Cajal (ICC)-like cells (ICC-L) by conventional transmission electron microscopy (TEM) and immuno-transmission electron microscopy (I-TEM) with antibodies directed towards CD117 and CD34. Two main types of interstitial cells were identified by TEM: ICC-L and fibroblast-like cells (FLC). ICC-L were bipolar with slender (0.04 microm) flattened dendritic-like processes, frequently forming a branching labyrinth network. Caveolae and short membrane-associated dense bands were present. Mitochondria, rough endoplasmic reticulum and Golgi apparatus were observed in the cell somata and cytoplasmic processes. Intermediate filaments were abundant but no thick filaments were found. ICC-L were interconnected by close appositions, gap junctions and peg-and-socket junctions (PSJ) but no specialised contacts to smooth muscle or nerves were apparent. FLC were characterised by abundant rough endoplasmic reticulum but no caveolae or membrane-associated dense bands were observed; gap junctions and PSJ were absent and intermediate filaments were rare. By I-TEM, CD34 gold immunolabelling was present in long cytoplasmic processes corresponding to ICC-L between muscle fascicles but CD117 gold immunolabelling was negative. Thus, ICC-like cells are present in the human detrusor. They are CD34-immunoreactive and have a myoid ultrastructure clearly distinguishable from fibroblast-like cells. ICC-L may be analogous to interstitial cells of Cajal in the gut.

CD34-positive interstitial cells of the human detrusor.

Interstitial cells of Cajal (ICC) are well described in the bowel wall. They are c-kit positive and play a role as pacemaker cells. Similar c-kit-positive cells have recently been described in the human bladder. The aim of this study was to characterize interstitial cells of the bladder detrusor using a panel of antibodies directed against CD117/c-kit, CD34, CD31, S100, tryptase, neurofilament, NSE, Factor-VIII and GFAP. A striking finding was an interstitial type of cell which is CD34 immunoreactive (CD34-ir) but CD117/c-kit negative. The cells have a tentacular morphology, enveloping and intermingling with individual muscle fasicles. Morphologically and immunohistochemically, they show no neurogenic, endothelial or mast cell differentiation. Transmission electron microscopy (TEM) showed the presence of interstitial cells with a round-to-oval nucleus, sparse perinuclear cytoplasm and long flattened processes, ramifying primarily in a bipolar fashion. Using immunoelectron microscopy (I-TEM) it was possible to view CD34 gold labelling of cells corresponding to interstitial cells. Although similar CD34-positive cells have been demonstrated in the bowel wall, they have never been described in the detrusor. The ontogeny and function of CD34-ir, a kit-negative cell, is unknown, but it may be involved in smooth muscle contraction.

Metabolic and inflammatory faecal markers in collagenous colitis.

OBJECTIVES: To evaluate the excretion of the inflammatory and metabolic faecal markers calprotectin, lactoferrin, and short-chain fatty acids in symptomatic and quiescent collagenous colitis. METHODS: Faecal samples from 21 patients with active collagenous colitis, 12 patients retested in remission, and 13 controls were analysed. Calprotectin was determined using an enzyme-linked immunosorbent assay. Lactoferrin was estimated by a latex agglutination test. Short-chain fatty acids were determined by steam distillation followed by gas-liquid chromatography. RESULTS: Calprotectin was increased in patients with active collagenous colitis [80 microg/g (6.25-1899)] (median and range) compared with patients with quiescent collagenous colitis [26 microg/g (6.25-340)], P=0.025 and controls [6.25 microg/g (6.25-99)], P=0.002. Eight patients (38%) with active collagenous colitis had normal levels of calprotectin. Lactoferrin was detected in one patient only. Concentrations of total short-chain fatty acids did not differ in patients with active collagenous colitis compared with quiescent collagenous colitis or controls (P=0.75), whereas concentrations of the branched-chain fatty acids were decreased in patients with active collagenous colitis versus controls (P<0.005). In-vitro incubations demonstrated increased ratios of acetate in patients with active and quiescent collagenous colitis compared with controls (P<0.05), with a corresponding decrease in branched-chain fatty acids ratios (P<0.05). CONCLUSION: Faecal calprotectin was increased in collagenous colitis; however, increased excretion was not a universal finding limiting the use of calprotectin as an inflammatory marker in collagenous colitis. Faecal lactoferrin was almost undetectable. Luminal fermentative conditions are altered in collagenous colitis. Fermentative alterations could be secondary to changes in substrate availability and intestinal transit time.

Small-bowel permeability in collagenous colitis.

OBJECTIVE: Collagenous colitis (CC) is a chronic inflammatory bowel disease that affects the colon. However, some patients with CC present with accompanying pathologic small-bowel manifestations such as coeliac disease, defects in bile acid absorption and histopathologic changes in small-intestinal biopsies, indicating that CC is a pan-intestinal disease. In small-intestinal disease, the intestinal barrier function may be impaired, and the permeability of the small intestine altered. The purpose of this research was to study small-bowel function in patients with CC as expressed by intestinal permeability. MATERIAL AND METHODS: Ten patients with CC and chronic diarrhoea participated in the study. Coeliac disease was excluded by small-bowel biopsy and/or serology. Intestinal permeability was assessed as urinary excretion (ratios) 2, 4 and 6 h after ingestion of 14C-labelled mannitol (14C-mannitol) and 99mTc-labelled diethylenetriamine-pentaacetic acid (99mTc-DTPA). Data were compared with the results from healthy controls. RESULTS: No difference was found between groups in urinary excretion of 14C-mannitol and 99mTc-DTPA after 2, 4 or 6 h, respectively. Likewise, no significant differences in the 99mTc-DTPA/14C-mannitol ratios between patients and controls were detected after 2 h: 0.030 (0.008-0.130) versus 0.020 (0.007-0.030), p = 0.19, after 4 h: 0.040 (0.009-0.180) versus 0.020 (0.008-0.040), p = 0.14 or after 6 h: 0.040 (0.012-0.180) versus 0.020 (0.010-0.040), p = 0.17. CONCLUSIONS: No alterations in intestinal permeability in patients with CC could be demonstrated. Impairment of the integrity of the mucosa of the small bowel and the presence of a general dysfunction of the small intestine in patients with CC seem unlikely.

Probiotic treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial with Lactobacillus acidophilus and Bifidobacterium animalis subsp. Lactis.

BACKGROUND: Probiotic treatment may be effective in diseases involving gut microflora and intestinal inflammation. In collagenous colitis (CC), a potential pathogenic role of the gut microflora has been proposed. The effect of probiotic treatment in CC is unknown. Our aim was to investigate the clinical effect of treatment with Lactobacillus acidophilus LA-5 and Bifidobacterium animalis subsp. lactis BB-12 (AB-Cap-10) in patients with CC. MATERIALS AND METHODS: Patients with CC and diarrhea were in a double-blind placebo-controlled study randomized (2:1) to AB-Cap-10 or placebo for 12 weeks. The primary end point was reduction in bowel frequency per week of >or=50%. Secondary end points were changes in bowel frequencies, stool consistency, stool weight, histopathology, and abdominal bloating and pain. RESULTS: Twenty-nine patients were randomized: 21 to probiotics and 8 to placebo. Reduction in bowel frequency per week of >or=50% occurred in 6 of 21 (29%) and in 1 of 8 (13%) patients receiving probiotic and placebo, respectively (P = 0.635). No differences between treatments were observed regarding the secondary end points. Post hoc analysis showed a median reduction in bowel frequency per week from 32 (range 18-84) to 23 (range 11-56; P < 0.005), a reduction in number of days with liquid stools per week from 6 days (range 0-7 days) to 1 day (range 0-7 days; P < 0.005), and an increase in number of days with solid stools per week (P < 0.05) in the AB-Cap-10 group. CONCLUSIONS: AB-Cap-10 had no significant effect on the chosen end points. Post hoc analysis demonstrated amelioration of clinical symptoms in the AB-Cap-10 group, indicating that probiotic treatment may potentially influence the disease course of CC.