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Background and Aims: Previous chromatographic analysis of colonic mucins from monozygotic twins with inflammatory bowel disease (IBD) suggested a genetic mucin alteration in ulcerative colitis (UC). This study explores this further by assessing mucosal expression of the oncofetal carbohydrate antigen TF (galactose beta1, 3 N-acetylgalactosamine alpha-), among the same IBD twins., Materials and Methods: Formalin fixed paraffin embedded rectal biopsies were studied from 22 monozygotic twin pairs with IBD. These included eight UC twin pairs and 14 Crohn's disease (CD) twin pairs, with six pairs concordant for disease and 16 unaffected twin siblings. Closely adjacent sections were assessed by peanut lectin histochemistry for TF expression and immunohistochemically for nuclear factor kappaB (NFkappaB) activation with investigators blinded to the diagnosis., Results: Unaffected twins were almost all TF positive (15/16) compared with 5/29 histologically normal controls (p<0.0001). Unaffected UC (7/8) and CD twins (8/8) were similarly TF positive. TF positivity was confined mainly to the superficial epithelium and absent from the stem cell compartment of the lower crypts, suggesting that glycosylation changes are acquired rather than genetically determined. Activated NFkappaB was present in the surface epithelium of mucosal biopsies from 13/14 unaffected IBD twins but in only 6/22 histologically normal controls (p=0.0004). All 22 affected IBD twins were TF positive and 18 were positive for activated NFkappaB., Conclusions: Altered mucosal glycosylation in unaffected identical twins of IBD patients was confirmed in this study. This occurred in both UC and CD twins. The changes are probably acquired rather than congenital and may reflect "preinflammatory" NFkappaB activation.

Background and Aims: An increased occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) is reported in unaffected members of families with Crohn's disease. Whether ASCA is a familial trait due to genetic factors or is caused by exposure to environmental factors is unknown. To assess the genetic influence of ASCA we studied its occurrence in a twin population., Patients and Methods: ASCA were analysed in 98 twin pairs with inflammatory bowel disease and were related to clinical phenotype and CARD15/NOD2 genotype., Results: ASCA were more common in Crohn's disease than in ulcerative colitis (40/70 (57%) twins v 5/43 (12%) twins). Associations with ileal Crohn's disease, stricturing/penetrating behaviour, and young age, but not CARD15/NOD2 were confirmed. ASCA were found in 1/20 (5%) healthy siblings in discordant monozygotic pairs with Crohn's disease compared with 7/27 (26%) in discordant dizygotic pairs. Using the intraclass correlation coefficient (ICC), no agreement in ASCA titres was observed in discordant twin pairs with Crohn's disease, in monozygotic (ICC = -0.02) or dizygotic (ICC = -0.26) pairs. In contrast, strong agreement was seen within concordant monozygotic twin pairs with Crohn's disease (ICC = 0.76)., Conclusions: These findings question the concept of ASCA as a marker of genetic susceptibility for Crohn's disease. The agreement in ASCA titres within concordant monozygotic twin pairs with Crohn's disease, suggests that the level of increase is genetically determined. We propose that ASCA are a marker of a response to an environmental antigen and that a specific gene(s) other than CARD15/NOD2 determines the level of response and perhaps also specific phenotypic characteristics.

Background: Lymphocytic colitis is characterised by chronic diarrhoea and specific microscopic changes in a macroscopically normal colonic mucosa. We report clinical features and treatment outcome in a large patient cohort., Methods: Patients were searched for in 24 Swedish gastroenterology clinics. The biopsy material was reassessed using strict histopathological criteria. Clinical data were obtained from medical notes., Results: Lymphocytic colitis was diagnosed in 199 cases. The female:male ratio was 2.4:1. Median age at diagnosis was 59 (48-70) years. The most frequent symptoms were diarrhoea (96%), abdominal pain (47%), and weight loss (41%). The course was chronic intermittent in 30% of patients, chronic continuous in 7%, and a single attack in 63%, and in these cases the disease duration was 6 (4-11) months. Seventy nine (40%) patients reported associated diseases, of which thyroid disorders, coeliac disease, and diabetes mellitus were the most common. In 34 first or second degree relatives of 24 (12%) patients, a family history of ulcerative colitis, Crohn's disease, collagenous colitis, or coeliac disease was reported. Drug induced disease was suspected in 19 (10%) patients. A non-significant peak of disease onset was seen in December-January. More than 80% of treated patients improved on corticosteroids, including budesonide., Conclusions: A family history of other bowel disorders is a new finding. The sudden onset and single attack of limited duration may support a possible infectious cause in some cases. Drugs may cause lymphocytic colitis.

Background: Microscopic colitis, including collagenous colitis and lymphocytic colitis, mainly affects middle aged and older subjects, with a female predominance in collagenous colitis. The diseases have previously been regarded as rare. We present an epidemiological study of microscopic colitis in a well defined Swedish population., Methods: Patients were retrospectively searched for in colonoscopy reports of those who had a colonoscopy in the period 1993-1998 for non-bloody diarrhoea. All colonic mucosal biopsies were reassessed using strict diagnostic criteria., Results: Biopsies from 1018 patients were reassessed. Fifty one (45 female) collagenous colitis patients and 46 (31 female) lymphocytic colitis patients were diagnosed. Median age at diagnosis was 64 years in collagenous colitis and 59 years in lymphocytic colitis. The mean annual incidence of collagenous colitis was 4.9/10(5) inhabitants (95% confidence interval (CI) 3.6-6.2/10(5)) and of lymphocytic colitis 4.4/10(5) inhabitants (95% CI 3.1-5.7/10(5)). The annual incidence of collagenous colitis increased from 3.7/10(5) in 1993-1995 to 6.1/10(5) in 1996-1998 (difference 2.4/10(5) (95% CI -0.3-5.1/10(5))) whereas the incidence of lymphocytic colitis increased from 3.1/10(5) to 5.7/10(5) (difference 2.6/10(5) (95% CI 0.1-5.2/10(5)))., Conclusions: The annual incidences of collagenous colitis and lymphocytic colitis are higher than considered previously and are now equal to the incidence of Crohn's disease in Sweden, and combined rates approach the incidence of ulcerative colitis. Microscopic colitis was diagnosed in 10% of all patients with non-bloody diarrhoea referred for colonoscopy and in almost 20% of those older than 70 years.

Background: A familial defect in intestinal barrier function has been found in Crohn's disease., Aim: To investigate possible genetic and environmental influences on this barrier defect by studying intestinal permeability in both relatives and spouses of patients with Crohn's disease., Subjects: The study included 39 patients with Crohn's disease, 34 healthy first degree relatives, and 22 spouses. Twenty nine healthy volunteers served as controls., Methods: Intestinal permeability was assessed as the lactulose:mannitol ratio in five hour urinary excretion after oral load, both before (baseline) and after ingestion of acetylsalicylic acid. The permeability response represents the difference between the two tests. A ratio above the 95th percentile for controls was classified as abnormal., Results: Baseline permeability was higher in patients and spouses than in controls. An abnormal baseline permeability was seen in 36% of the patients, 23% of the spouses, 18% of the relatives, and 3% of the controls. After ingestion of acetylsalicylic acid, permeability increased significantly in all groups. Relatives were similar to patients with regard to permeability after exposure to acetylsalicylic acid, whereas spouses were similar to controls. The proportions with an abnormal permeability response to acetylsalicylic acid were 32% in patients, 14% in spouses, 41% in relatives, and 3% in controls. CONCLUSION The findings suggest that baseline permeability is determined by environmental factors, whereas permeability provoked by acetylsalicylic acid is a function of the genetically determined state of the mucosal barrier, and support the notion that environmental and hereditary factors interact in the pathogenesis of Crohn's disease.

Background: Data on collagenous colitis have been based on a limited number of patients., Aims: To obtain more information on this disease from a register set up at Orebro Medical Center Hospital., Patients and Methods: Twenty five Swedish hospitals have contributed to this patient register, which comprises 163 histopathologically verified cases. Clinical data were retrospectively analysed., Results: Collagenous colitis followed a chronic intermittent course in most cases (85%) with a sudden onset in 42%. Symptoms were chronic watery diarrhoea, often nocturnal (27%), abdominal pain (41%), and weight loss (42%). Sixty six patients (40%) had one or more associated diseases. Routine laboratory data were mostly normal. The median age at diagnosis was 55 (range 16-86) years, but 25% of the patients were younger than 45 years. Seven patients died of unrelated diseases. The response rate for sulphasalazine was 59%, and 50% and 40% for mesalazine and olsalazine. Prednisolone was most effective with a response rate of 82%, but the required dose was often high and the effect was not sustained after withdrawal. Antibiotics were efficient in 63%. Cholestyramine and loperamide had response rates of 59% and 71% respectively., Conclusions: Collagenous colitis follows a chronic continuous course. Symptoms can be socially disabling, but the disease does not seem to have a malignant potential. A plan for the treatment of a newly diagnosed patient with collagenous colitis is proposed.

Background: The aetiology and pathogenesis of collagenous colitis are unknown. Autoimmunity has been suggested, but no serological findings have supported such a theory., Aims and Methods: Serum from 38 collagenous colitis patients and 38 matched healthy controls was analysed for autoantibodies--that is, antinuclear antibodies, antineutrophil cytoplasmic antibodies, smooth muscle and mitochondrial antibodies, rheumatoid factor and antibodies to thyroglobulin and microsomal antigen, together with antibodies to endomysium, gliadin, and cardiolipin. The serum values of IgA, IgG, IgM, and IgG-subclasses, and complement factors C3 and C4 were also determined., Results: In patients with collagenous colitis the mean value of IgM was significantly increased 2.5 g/l (95% CI; 1.9, 3.2) compared with 1.4 g/l (95% CI; 1.2, 1.7) in controls (p = 0.002). Antinuclear antibodies occurred in nine of 38 patients compared with three of 38 controls, this difference was not statistically significant (p = 0.11). The results of all other immunoglobulins, complement factors, and specific antibodies showed no statistical difference between patients and controls., Conclusions: No firm evidence for an autoimmune genesis in collagenous colitis is found in this study, although the findings of a positive ANA-titre in some patients and an increased IgM level might give some support for this hypothesis.

The incidence and prevalence of collagenous colitis are unknown. An epidemiological study was undertaken between 1984-93. All patients living in the immediate catchment area of Orebro Medical Center Hospital with the diagnosis collagenous colitis were identified. Biopsy specimens classified as unspecific intestinal fibrosis were re-examined to identify cases not correctly diagnosed at first. Medical records were scrutinised and colorectal biopsy specimens re-evaluated. Thirty patients with collagenous colitis were diagnosed during the study period. The female:male ratio was 9:1. The median age at diagnosis was 64 (28-78) years. The prevalence at 31 December 1993, was 15.7/10(5) inhabitants (95% CI; 9.8 to 21.6/10(5)). The mean annual incidence during the period 1984-93 was 1.8/10(5) inhabitants (95% CI; 1.2 to 2.4/10(5)). A peak incidence was found in women 70-79 years old. Collagenous colitis occurs mainly in middle aged women, and the frequency is higher than earlier anticipated. The prevalence and incidence is similar to primary biliary cirrhosis. In women 70-79 years of age, the incidence for collagenous colitis approaches the incidence for ulcerative colitis.

Perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) have been demonstrated in patients with ulcerative colitis and in a higher frequency than expected in their first degree relatives. A hypothesis was proposed that P-ANCA is genetically determined and may represent a subclinical marker of genetic susceptibility to ulcerative colitis. This study analysed P-ANCA in monozygotic twins with inflammatory bowel disease to evaluate this hypothesis further. P-ANCA was analysed with indirect immunofluorescence technique in 12 monozygotic twin pairs with ulcerative colitis and 14 twin pairs with Crohn's disease. Furthermore, the study included 21 non-twin patients with ulcerative colitis, 18 non-twin patients with Crohn's disease, and 52 healthy controls matched for sex and age. In ulcerative colitis P-ANCA occurred in nine of 14 (64.3%) monozygotic twins and in 13 of 21 (61.9%) non-twin cases, which was significantly different compared with healthy controls who were positive in three of 52 (5.8%) cases (p < 0.0001). P-ANCA was found in two of 10 (20%) healthy twin siblings to twins with ulcerative colitis, which was not significantly different from healthy controls (p = 0.18). The results in Crohn's disease did not differ from healthy controls. Previous findings of P-ANCA occurring in ulcerative colitis but not in Crohn's disease are supported. This study does not support the hypothesis that P-ANCA is a subclinical marker of genetic susceptibility to ulcerative colitis.

To evaluate the optimum dose of olsalazine for maintaining remission in ulcerative colitis, 198 patients in remission for more than three months were randomly assigned to receive 0.5 g, 1.0 g, or 2.0 g/day for 12 months. A dose-ranging effect was detected in the per protocol analysis, with remission rates of 60% (0.5 g), 70% (1.0 g), and 78% (2.0 g) (p = 0.03, trend in proportions). The higher dose was most effective in patients with proctitis (90% remission on 2 g/day, p = 0.03) or those in remission for less than 12 months before the trial (88% remission on 2 g/day, p = 0.0006). There was little dose-ranging effect in patients with extensive colitis or those in remission for more than 12 months. Diarrhoea necessitated treatment withdrawal in 12%. The optimal dose of olsalazine for maintaining remission in ulcerative colitis is 1 g/day. For patients with proctitis or recent relapse, 2 g/day may be preferable, although the dose seems to be less important in patients with more extensive disease or those in long term remission.

A total of 61 human gastric isolates of Helicobacter pylori were studied for their ability to induce an oxidative burst in human neutrophils measured by luminol enhanced chemiluminescence. About one third of the strains induced strong and rapid chemiluminescence in neutrophils even without serum opsonins and agglutinated these cells on glass slides within two minutes. For other strains complement was required, although even then the reactions remained at a lower level. The activating and agglutinating property was bound to the cells, heat labile, and sensitive to several enzymes but resistant to acid. Strains possessing such activity were more common in patients with peptic ulcer disease than in patients with active chronic gastritis only (p = 0.0261, Fisher's exact test, two tailed). The activity shown might be a new indicator for ulcerogenic strains and could also partly explain the accumulation of neutrophils in the gastric mucosa during H pylori infection.

Serum samples from 26 monozygotic twin pairs concordant or discordant with regard to inflammatory bowel disease, and rectal biopsies from 42 twins of the same subject group, were examined for IgG subclasses. They were all compared with normal controls. Almost all affected twins were in clinical remission. Paired immunofluorescence staining of the rectal mucosa showed that those with ulcerative colitis had a significantly higher (p < 0.01) proportion of IgG1 producing mucosal immunocytes than normal controls (78.1% v 55.9%). Conversely, the IgG2 cell fraction was significantly reduced (15.9% v 34.6%). Healthy twins from ulcerative colitis pairs tended to show a raised proportion of IgG1 cells and the IgG2 cell fraction was significantly reduced (p < 0.05). In discordant ulcerative colitis twin pairs, no difference appeared in the cellular IgG subclass pattern between healthy and affected twins. Furthermore, the proportion of IgG1 in these healthy and diseased twins showed good correlation (T = 0.867). The results in rectal mucosa of twins with Crohn's disease were widely scattered and affected twins did not differ significantly from normal controls. Healthy twins, however, showed a marginally raised IgG1 cell proportion, but no correlation was seen between the IgG subclass fractions in discordant Crohn's disease twin pairs. The serum concentrations of IgG1 and IgG2 did not differ from normal controls in twins of either category. These results suggested that in ulcerative colitis, the aberrant mucosal production of IgG1 and IgG2 does not depend on active disease, but is apparently at least partially explained by a genetic impact. Conversely, the mucosal IgG subclass pattern in Crohn's disease appears to be determined mainly by exogenous variables.

To assess whether dietary antigens play a role in inflammatory bowel disease, 26 monozygotic twin pairs with inflammatory bowel disease and 52 healthy controls were investigated for serum antibodies (IgA, IgG, IgM) against ovalbumin, betalactoglobulin, gliadin, whole yeast (Saccharomyces cerevisiae) and yeast cell wall mannan. The twins were made up of five pairs concordant and nine pairs discordant for Crohn's disease, and two pairs concordant and 10 pairs discordant for ulcerative colitis. Two patients with Crohn's disease had a slight increase in disease activity, the others were in clinical remission. Two striking observations were made: first, individuals with ulcerative colitis were indistinguishable from healthy twins, and controls except for the response to gliadin. Both healthy and diseased twins had higher IgA levels to gliadin than controls. Second, twins who had developed Crohn's disease displayed higher antibody titres towards yeast cell wall mannan in particular, but also to whole yeast (Saccharomyces cerevisiae) of all antibody types (IgA, IgG, and IgM). In contrast, the response to gliadin, ovalbumin, and betalactoglobulin did not differ from healthy twins and was even lower than in the controls. The results argue against an increased systemic antigen presentation caused by an impaired mucosal barrier in the inflammatory bowel disease. Rather, they suggest that yeast cell wall material--that is, mannan, or some antigen rich in mannose and cross reacting with mannan, may play an aetiological role in Crohn's disease, but not in ulcerative colitis. The increases in IgA and IgM, as well as IgG suggest that local and systemic immune systems are selectively activated by antigen(s) present in the cell wall of baker's yeast.

The effects of smoking on the localisation and clinical course of Crohn's disease is evaluated in 231 patients. Heavy smokers (greater than 10 cigarettes/day) had an increased risk of operation at least once--odds ratios for heavy smokers compared with never smokers after five and 10 years were 1.14 and 1.24 respectively (p = 0.03 and p = 0.017). The risk of further operations was even higher and after 10 years the odds ratio was 1.79 (p = 0.015). The accumulated number of fistulae and/or abscesses was higher for smokers than for never smokers (p = 0.046). Patients with a high life time tobacco exposure (greater than 150 cigarette years) and heavy smokers (greater than 10 cigarettes/day) had small bowel disease more often than patients with lower life time exposure (less than or equal to 150 cigarette years) and patients smoking less than or equal to 10 cigarettes/day (p = 0.002 and p = 0.045 respectively). The course of Crohn's disease analysed in different ways was unfavourable for smokers, especially heavy smokers. Patients with Crohn's disease should be dissuaded from smoking.

Azodisal sodium is a highly effective means of oral delivery of 5-amino-salicylic acid to the colonic mucosa. Administration of this drug to patients intolerant of sulphasalazine, however, occasionally results in liquid stools. In preliminary experiments, which comprised 10 healthy volunteers treated with colectomy for ulcerative colitis, ileostomy fluid output increased (p less than 0.001) during oral intake of azodisal sodium (1 g/day). In a double blind, placebo controlled crossover study, comprising eight similar volunteers, ileostomy fluid output increased (p less than 0.05) in a dose related manner during intake of azodisal sodium (1 g/day vs 2 g/day) compared with placebo or sulphasalazine (2 g/day). Concentrations of prostaglandin (PG)F2 alpha in free ileal water determined by equilibrium in vivo dialysis of ileostomy contents decreased (p less than 0.05) during intake of azodisal sodium (2 g/day), whereas concentrations of PGE2 and the output of PGE2, PGF2 alpha, and 'PGE2 + PGF2 alpha' remained unchanged. Thus increased formation of PGs is apparently not the cause of increased ileostomy fluid output associated with azodisalicylate intake.

Sixty two patients with a clinical suspicion of biliary dyskinesia were investigated with endoscopic manometry of the sphincter of Oddi before and after intravenous injection of cholecystokinin or ceruletide. In 52 patients injection was followed by decreased pressure in the sphincter of Oddi; 43 of these had normal prestimulatory values (group I), while the values were raised in the other nine patients (group II). A paradoxical response to intravenous injection was observed in 10 women (group III): increased baseline sphincteric pressure occurred in eight and increase in the amplitude of phasic contractions in four patients. The prestimulatory sphincteric pressure was raised in five and normal in the remaining patients. Eight patients were treated with papillotomy (seven) or balloon dilatation of the sphincter (one). They experienced relief of pain during a follow up period of 11-16 months. Intravenous injection of cholecystokinin or ceruletide may disclose a special type of biliary dyskinesia even in patients with normal prestimulatory manometric findings. Hormone injection increases the diagnostic yield of endoscopic manometry in patients suspected of biliary dyskinesia.

By running the Swedish twin registry containing about 25,000 pairs of twins of the same sex together with the central national diagnosis register of hospital inpatients, 80 twin pairs suffering from inflammatory bowel disease were found. In the ulcerative colitis group one of 16 monozygotic pairs was concordant for the disease, but all the other 20 pairs (dizygotic or unknown zygosity) were discordant. In the Crohn's disease group eight of 18 monozygotic pairs and one of 26 dizygotic pairs were concordant. The proband concordance rate among monozygotic twins was 6.3% for ulcerative colitis and 58.3% for Crohn's disease. The calculated heritability of liability based on monozygotic pairs was 0.53 and 1.0 respectively. Thus heredity as an aetiological factor is stronger in Crohn's disease than in ulcerative colitis. Monozygotic twins with Crohn's disease were more likely to be smokers than monozygotic twins with ulcerative colitis. Smoking did not explain the discordance of twin pairs with either ulcerative colitis, or Crohn's disease. The combination of identical heredity and similar smoking habit is not sufficient to cause disease.

A population case controlled study of smoking habits at the time of diagnosis was done in 260 patients with ulcerative colitis and 144 with Crohn's disease. Smokers had a decreased risk of acquiring ulcerative colitis in comparison with never smokers (relative risk 0.7) which appeared to be dose dependent. In former smokers a rebound effect was seen, especially in former heavy smokers, where the risk was sharply increased (relative risk 4.4). No sex difference was recorded. Smoking doubled the risk of acquiring Crohn's disease without any dose dependent pattern. In former smokers a non-significantly increased risk was observed. This might be caused by a carry over effect after stopping smoking, however, which possibly is reduced by time. No sex difference was seen.