Diverticular disease in Scotland: 2000-2010.

AIM: Symptomatic diverticular disease (DD) may be increasing in incidence in western society particularly in younger age groups. This study aimed to describe hospital admission rates and management for DD in Scotland between 2000 and 2010. METHOD: Data were obtained from the Scottish Morbidity Records (SMR01). The study cohort included all patients with a hospital admission and a primary diagnosis of DD of the large intestine (ICD-10 primary code K57). RESULTS: Scottish NHS hospitals reported 90 990 admissions for DD (in 87 314 patients) from 2000 to 2010. The annual number of admissions increased by 55.2% from 6591 in 2000 to 10,228 in 2010, an average annual increase per year of 4.5%. Most of the increase attributable to DD was due to elective day cases (3618 in 2000; 6925 in 2010) a likely consequence of a greater proportion of the population accessing colonoscopy over that time period. There was an 11% increase in inpatient admissions (2973-3303), 60% of these patients being women. Admissions in younger age groups increased proportionally in the later years of the study, and there was an association between DD admissions and greater deprivation. Despite an increase in complicated DD from 22.9% in 2000 to 27.1% in 2010 and a 16.8% increase in emergency inpatient admissions, the rate of surgery fell during the period of study. CONCLUSION: This report supports findings of other population-based studies of western countries indicating that DD is an increasing burden on health service resources, particularly in younger age groups.

Temporal Trends in Surgical Resection Rates and Biologic Prescribing in Crohn's Disease: A Population-based Cohort Study.

BACKGROUND: The use of biologic therapy for Crohn's disease [CD] continues to evolve, however, the effect of this on the requirement for surgery remains unclear. We assessed changes in biologic prescription and surgery over time in a population-based cohort. METHODS: We performed a retrospective cohort study of all 1753 patients diagnosed with CD in Lothian, Scotland, between January 1, 2000 and December 31, 2017, reviewing the electronic health record of each patient to identify all CD-related surgery and biologic prescription. Cumulative probability and hazard ratios for surgery and biologic prescription from diagnosis were calculated and compared using the log-rank test and Cox regression analysis stratified by year of diagnosis into cohorts. RESULTS: The 5-year cumulative risk of surgery was 20.4% in cohort 1 [2000-2004],18.3% in cohort 2 [2005-2008], 14.7% in cohort 3 [2009-2013], and 13.0% in cohort 4 [2014-2017] p <0.001. The 5-year cumulative risk of biologic prescription was 5.7% in cohort 1, 12.2% in cohort 2, 22.0% in cohort 3, and 44.9% in cohort 4 p <0.001. CONCLUSIONS: The increased and earlier use of biologic therapy in CD patients corresponded with a decreasing requirement for surgery over time within our cohort. This could mean that adopting a top-down or accelerated step-up treatment strategy may be effective at reducing the requirement for surgery in newly diagnosed CD.

Fecal calprotectin predicts the clinical course of acute severe ulcerative colitis.

OBJECTIVES: Calprotectin is a granulocyte neutrophil-predominant cytosolic protein. Fecal concentrations are elevated in intestinal inflammation and may predict relapse in quiescent inflammatory bowel disease. We aim to investigate fecal calprotectin (FC) as a biomarker in predicting the clinical course of acute severe ulcerative colitis (ASUC). METHODS: In 90 patients with ASUC requiring intensive in-patient medical therapy (January 2005-September 2007), we investigated the discriminant ability of FC to predict colectomy and corticosteroid and infliximab nonresponse. All patients received parenteral corticosteroids as first-line treatment; 21 (23.3%) were also treated with infliximab (5 mg/kg), after failure of corticosteroid therapy. RESULTS: Of 90 patients, 31 (34.4%) required colectomy, including 11 (52.4%) of those treated with infliximab. Overall FC was high (1,020.0 microg/g interquartile range: 601.5-1,617.5). FC was significantly higher in patients requiring colectomy (1,200.0 vs. 887.0; P=0.04), with a trend toward significance when comparing corticosteroid nonresponders and responders (1,100.0 vs. 863.5; P=0.08), as well as between infliximab nonresponders and responders (1,795.0 vs. 920.5; P=0.06). Receiver-operator characteristic curve analysis yielded an area under the curve of 0.65 to predict colectomy (P=0.04), with a maximum likelihood ratio of 9.23, specificity 97.4%, and sensitivity 24.0% at a cutoff point of 1,922.5 microg/g. Kaplan-Meier analyses showed that using 1,922.5 microg/g over a median follow-up of 1.10 years, 87% of patients will need subsequent colectomy. CONCLUSIONS: This is the first data set to demonstrate that FC levels are dramatically elevated in severe UC. These data raise the possibility that this biomarker can predict response to first or second-line medical therapy in this setting.

Anti-Saccharomyces cerevisiae antibodies status is associated with oral involvement and disease severity in Crohn disease.

OBJECTIVES: To determine anti-Saccharomyces cerevisiae antibodies (ASCA) status and its relation to disease phenotype in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: A total of 301 Scottish patients with early-onset IBD-197 Crohn disease (CD), 76 ulcerative colitis (UC), 28 indeterminate colitis (IC)-and 78 healthy control individuals were studied. ASCA status (IgA, IgG) was determined by enzyme-linked immunosorbent assay. ASCA status was then analyzed in relation to CD phenotype. RESULTS: Patients with CD had a higher prevalence of ASCA than patients with UC and healthy controls: 82/197 versus 12/76, odds ratio (OR) 3.80 (1.93-7.50) and 82/197 versus 6/78, OR 8.56 (3.55-20.62), respectively. Univariate analysis showed that positive ASCA status was associated with oral CD (17/25 vs 59/153, OR 3.39 [1.38-8.34]), perianal CD (39/77 vs 38/108, OR 1.89 [1.04-3.44]) and the presence of granulomata (63/132 vs 15/52, OR 2.25 [1.13-4.48]) and also with markers of disease severity: raised C-reactive protein (44/90 vs 12/49, OR 2.95[1.36-6.37]), hypoalbuminemia (44/85 vs 20/74, OR 2.28[1.19-4.37]), and surgery (27/49 vs 54/147, OR 2.11 [1.10-4.06]). From multivariate analysis, the presence of oral disease (adjusted P = 0.001, OR 22.22 [3.41-142.86]) and hypoalbuminemia (adjusted P = 0.01, OR 4.78 [1.40-16.39]) was found to be independently associated with ASCA status. No association was demonstrated between ASCA and IBD candidate genes. CONCLUSIONS: Patients with CD had a higher prevalence of ASCA than did other patients with IBD. ASCA status described patients with CD who had a specific phenotype, showing an association with markers of disease severity and oral CD involvement.

Regional variation in gene expression in the healthy colon is dysregulated in ulcerative colitis.

OBJECTIVE: To investigate differential intestinal gene expression in patients with ulcerative colitis and in controls. DESIGN: Genome-wide expression study (41,058 expression sequence tags, 215 biopsies). SETTING: Western General Hospital, Edinburgh, UK, and Genentech, San Francisco, USA. PATIENTS: 67 patients with ulcerative colitis and 31 control subjects (23 normal subjects and 8 patients with inflamed non-inflammatory bowel disease biopsies). INTERVENTIONS: Paired endoscopic biopsies were taken from 5 specific anatomical locations for RNA extraction and histology. The Agilent microarray platform was used and confirmation of results was undertaken by real time polymerase chain reaction and immunohistochemistry. RESULTS: In healthy control biopsies, cluster analysis showed differences in gene expression between the right and left colon. (chi(2) = 25.1, p<0.0001). Developmental genes, homeobox protein A13 (HOXA13), (p = 2.3x10(-16)), HOXB13 (p<1x10(-45)), glioma-associated oncogene 1 (GLI1) (p = 4.0x10(-24)), and GLI3 (p = 2.1x10(-28)) primarily drove this separation. When all ulcerative colitis biopsies and control biopsies were compared, 143 sequences had a fold change of >1.5 in the ulcerative colitis biopsies (0.01>p>10(-45)) and 54 sequences had a fold change of <-1.5 (0.01>p>10(-20)). Differentially upregulated genes in ulcerative colitis included serum amyloid A1 (SAA1) (p<10(-45)) the alpha defensins 5 and 6 (DEFA5 and 6) (p = 0.00003 and p = 6.95x10(-7), respectively), matrix metalloproteinase 3 (MMP3) (p = 5.6x10(-10)) and MMP7 (p = 2.3x10(-7)). Increased DEFA5 and 6 expression was further characterised to Paneth cell metaplasia by immunohistochemistry and in situ hybridisation. Sub-analysis of the inflammatory bowel disease 2 (IBD2) and IBD5 loci, and the ATP-binding cassette (ABC) transporter genes revealed a number of differentially regulated genes in the ulcerative colitis biopsies. CONCLUSIONS: Key findings are the expression gradient in the healthy adult colon and the involvement of novel gene families, as well as established candidate genes in the pathogenesis of ulcerative colitis.

Real-world Effectiveness and Safety of Vedolizumab for the Treatment of Inflammatory Bowel Disease: The Scottish Vedolizumab Cohort.

BACKGROUND & AIMS: Vedolizumab is an anti-a4b7 monoclonal antibody that is licensed for the treatment of moderate to severe Crohn's disease and ulcerative colitis. The aims of this study were to establish the real-world effectiveness and safety of vedolizumab for the treatment of inflammatory bowel disease. METHODS: This was a retrospective study involving seven NHS health boards in Scotland between June 2015 and November 2017. Inclusion criteria included: a diagnosis of ulcerative colitis or Crohn's disease with objective evidence of active inflammation at baseline (Harvey-Bradshaw Index[HBI] ≥5/Partial Mayo ≥2 plus C-reactive protein [CRP] >5 mg/L or faecal calprotectin ≥250 µg/g or inflammation on endoscopy/magnetic resonance imaging [MRI]); completion of induction; and at least one clinical follow-up by 12 months. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, and deep remission [clinical remission plus mucosal healing]. Rates of serious adverse events were described quantitatively. RESULTS: Our cohort consisted of 180 patients with ulcerative colitis and 260 with Crohn's disease. Combined median follow-up was 52 weeks (interquartile range [IQR] 26-52 weeks). In ulcerative colitis, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 57.4%, 47.3%, and 38.5%, respectively. In Crohn's disease, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 58.4%, 38.9%, and 28.3% respectively. The serious adverse event rate was 15.6 per 100 patient-years of follow-up. CONCLUSIONS: Vedolizumab is a safe and effective treatment for achieving both clinical remission and mucosal healing in ulcerative colitis and Crohn's disease.

Detailed assessment of NOD2/CARD15 exonic variation in inflammatory bowel disease in Scotland: implications for disease pathogenesis.

The high incidence of Scottish Crohn's disease (CD) is not explained by the common three NOD2/CARD15 variants. We aimed to identify population-specific NOD2/CARD15 coding variants. A total of 1478 (320 inflammatory bowel disease patients <16 years, 343 adult CD patients, 542 parents and 273 controls). All NOD2/CARD15 exons were sequenced in 24 CD patients. Sequencing identified 18 single-nucleotide polymorphisms (SNPs) including 4 non-synonymous coding SNPs altering the structure of the Leucine-rich region--two were well established (1007-/C and 908G/R). Two other variants, valine955isoleucine (955V/I) and methionine863valine (863M/V), were genotyped in all subjects. 863M/V carriage was not significantly higher in CD patients vs controls (1.35 vs 0.37%, P=0.27). 955V/I carriage was no higher in CD or ulcerative colitis patients (12.8 and 15.8%, respectively) compared to controls (16.2%). Transmission disequilibrium test analysis was negative. 955V/I carriage was higher in indeterminate colitis patients (n=29) compared to controls (41.4 vs 16.2%, P=0.001, OR=3.6 (1.6-8.2)). Population-specific NOD2/CARD15 exonic variants do not account for the high-CD prevalence in Scotland.

Autophagy gene ATG16L1 influences susceptibility and disease location but not childhood-onset in Crohn's disease in Northern Europe.

BACKGROUND: The rs2241880A/G variant of the ATG16L1 gene has been associated with susceptibility to ileal Crohn's disease (CD) in adults. Our aim was to assess whether germline variation of ATG16L1 acts as an independent determinant of susceptibility to childhood-onset CD in the high-incidence Scottish population. METHODS: In all, 2195 subjects (361 children (inflammatory bowel disease [IBD] diagnosis <17 years), their parents (n = 634), 855 adult IBD patients, and 345 controls were genotyped. Case-control analysis was powered to detect effect sizes with an odds ratio (OR) >1.39 in pediatric CD. Case-control analysis, transmission disequilibrium testing (TDT), analysis of variance (ANOVA) of growth parameter z-scores, Kruskal-Wallis test (age at diagnosis), and multifactorial genotype-phenotype analysis (Montreal classification) were performed. 7.8% of pediatric CD patients and 37.2% of adult CD patients had pure ileal disease. RESULTS: We confirmed the association of the rs2241880G-allele with adult-onset CD (60.7% versus controls 53.9%, P = 0.01, OR 1.32, 95% confidence interval [CI] 1.07-1.63) in contrast to childhood-onset CD (54.1% versus controls, P = 0.95, OR 1.01, 95% CI 0.80-1.26). TDT analysis was negative. Genotype-phenotype analysis demonstrated an association of pure ileal disease with the rs2241880G-allele (P = 0.02, OR 1.34, 95% CI 1.03-1.74). Using binary logistic regression analysis we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (P = 0.03, OR 2.43, 95% CI 1.05-5.65). ATG16L1 genotype did not influence age at CD diagnosis. ANOVA of z-scores of height, weight, and body mass index (BMI) at CD diagnosis in children showed no association with genotype. CONCLUSIONS: The ATG16L1 variant is associated with susceptibility to adult CD in Scotland, but not early-onset disease. These contrasting effects are primarily driven by differences in disease location between early-onset and adult-onset disease.

Contribution of the NOD1/CARD4 insertion/deletion polymorphism +32656 to inflammatory bowel disease in Northern Europe.

BACKGROUND: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4+32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4+32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations. METHODS: A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4+32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype-phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD. RESULTS: In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P > 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative. CONCLUSIONS: This variant allele of NOD1/CARD4+32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.

A retrospective analysis of the efficacy and safety of infliximab as rescue therapy in acute severe ulcerative colitis.

BACKGROUND: Forty per cent of patients with acute severe ulcerative colitis will not respond to intravenous corticosteroids and require second-line medical therapy or colectomy. A recent controlled trial has suggested that infliximab may be effective as rescue therapy. AIM: To assess the value of infliximab as rescue therapy for acute severe colitis in a retrospective cohort of ulcerative colitis patients in Scotland. METHODS: All patients satisfied Truelove and Witts criteria on admission, failed to respond to intravenous corticosteroids and received infliximab (5 mg/kg) as rescue therapy. Response was defined as need for colectomy at hospital discharge and by 90 days. RESULTS: A total of 39 patients (median age 31.7 years) were treated. 26/39 (66%) responded, avoiding colectomy during the acute admission, and were followed up for a median of 203 days (Interquartile range = 135.5-328.5). Hypoalbuminaemia was a consistent predictor of non-response on univariate and multivariate analysis. At day 3 of intravenous steroids, 9/18 (50.0%) with serum albumin <34 g/L had urgent colectomy vs. 1/13 (7.7%) >or=34 g/L (P = 0.02, OR = 12.0, C.I. 1.28-112.7). Two serious adverse events occurred - one death due to Pseudomonas pneumonia, and one post-operative fungal septicaemia. CONCLUSIONS: Infliximab represents a moderately effective rescue therapy for patients with acute severe ulcerative colitis. Serious adverse events, including death, do occur and should be discussed with patients prior to therapy.

The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort.

BACKGROUND: Corticosteroids remain the mainstay of first-line therapy in active inflammatory bowel disease. AIMS: To determine the clinical outcome after the first corticosteroid-therapy and to identify factors which predict response/failure. METHODS: 216 (136 ulcerative colitis and 80 Crohn's disease) patients were identified in this 5-year inception cohort. The outcomes of early (30 days) and late (1 year) responses were used. Multivariate analyses were performed to identify factors associated with outcome. RESULTS: 86 (63%) and 60 (75%) ulcerative colitis and Crohn's disease required corticosteroid therapy, respectively. In ulcerative colitis, at 30 days, 69 (51%), 42 (31%) and 25 (18%) patients demonstrated complete response, partial response and no response, respectively. For Crohn's disease, these outcomes were observed in 32 (40%), 28 (35%) and 20 (25%). After 1 year, 75 (55%), 23 (17%) and 29 (21%) patients with ulcerative colitis demonstrated prolonged response, corticosteroid-dependence or required surgery, respectively. For Crohn's disease, these outcomes were observed in 30 (38%), 19 (24%) and 27 (35%) patients. Extensive ulcerative colitis was a predictor of surgery (P = 0.001, OR: 15.2). In Crohn's disease, inflammatory disease behaviour was negatively associated with surgery (P = 0.02, OR: 0.13). CONCLUSION: Although corticosteroids are effective, dependence/resistance remains common. Patients with extensive ulcerative colitis and fistulizing/stricturing Crohn's are most at risk of failing corticosteroid therapy.

Predicting outcome in acute severe ulcerative colitis: comparison of the Travis and Ho scores using UK IBD audit data.

BACKGROUND: Acute severe ulcerative colitis is categorised using the Truelove & Witts criteria. The Travis and the Ho scores are calculated following 72 h of steroid treatment to identify patients at risk of failing steroid therapy who require colectomy or second-line medical therapy. AIM: To compare the Travis and the Ho scores in a large unselected cohort to determine which might be more clinically relevant. METHODS: We analysed 3049 patients with ulcerative colitis from the 2010 round of the UK IBD audit of which 984 had acute severe ulcerative colitis. 420 patients had sufficient data for analysis. Patients were allocated into either a Travis high- or low-risk group and either a Ho high-, intermediate- or low-risk group. We assessed whether further medical or surgical intervention and outcomes varied between groups. RESULTS: High-risk patients in Travis and the Ho groups, when compared to lower risk groups, were more likely to fail steroid therapy: 64.5% (131/203) vs. 38.7% (84/217) (P < 0.0001) for Travis and 66.2% (96/145) vs. 46.7% (85/182) vs. 36.6% (34/93) (P < 0.0001) for Ho. They were also more likely to undergo surgery 34.0% (69/203) vs. 9.7% (21/217) for Travis and 33.1% (48/145) vs. 17.0% (31/182) vs. 11.8% (11/93) (P < 0.0001) for Ho. Travis high patients were more likely to be refractory to second-line medical therapy: 44.6% (37/83) vs. 20.0% (9/45) (P = 0.01). CONCLUSIONS: Patients identified as high risk using the Travis or the Ho scoring systems are more likely to be resistant to IV steroids and require surgery. Risk of surgery in both high-risk populations is lower than previously reported.

An analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn's disease.

BACKGROUND: 59-81% of patients given infliximab for Crohn's disease will respond. Although now in widespread use, little consensus exists regarding the optimal place in patient care. Recently developed guidelines have identified need for markers that predict response. AIMS: We aimed to identify markers of response to infliximab given for Crohn's disease. METHODS: Markers of response (defined at 4 weeks) were prospectively assessed in 74 infliximab-treated patients with Crohn's disease. Patients were followed-up to 1 year. RESULTS: Fifty-four of 74 (73%) patients responded. Univariate analysis identified that smokers were less likely to respond than non-smokers [P = 0.005, odds ratio (OR) 0.22]. Patients established on immunosuppression (P = 0.034, OR 7.31) and with isolated colonic disease (P = 0.042, OR 3.83) were more likely to respond. Multiple logistic regression confirmed smoking (P = 0.035, OR 0.24) and colonic disease (P = 0.035, OR 4.87) as independent markers of response. One-year relapse rates differed significantly between smokers and non-smokers (100% vs. 39.6%, P = 0.0026, relative risk 3.2) and between patients established on immunomodulators or not (58.0% vs. 92.8%, P = 0.0054, relative risk 2.6). CONCLUSIONS: Smoking has a strong adverse effect on the response rates and maintenance of response to infliximab. Patients on immunomodulators have a more favourable short- and long-term response. These results have important implications for clinical practice.

Review article: is clinical remission the optimum therapeutic goal in the treatment of Crohn's disease?

Currently, the therapeutic end-point in the treatment of Crohn's disease is the remission of symptoms, but recent data confirm that mucosal inflammation may continue in the absence of symptoms. Furthermore, emerging evidence indicates that such subtle, sub-clinical mucosal inflammation leads to clinical relapse. The assessment of mucosal inflammation has become easier with the availability of faecal calprotectin assay. Current anti-inflammatory therapy often leaves low-grade mucosal inflammation untreated, and therefore recurrent relapses occur. We need to investigate whether the therapeutic end-point of anti-inflammatory medications needs to be more rigorous and to aim at complete mucosal healing, confirmed by the normalization of mucosal inflammatory markers such as faecal calprotectin concentrations. Immunosuppressive therapy with azathioprine/ 6-mercaptopurine currently offers the best mucosal healing treatment with reduction of relapses, but newer biological agents might offer less toxic therapy. Clinical trials to test the feasibility and efficacy of such a paradigm shift in the medical management of Crohn's disease are now warranted.

Clinical use of Infliximab in Crohn's disease: the Edinburgh experience.

UNLABELLED: Infliximab is an established treatment for steroid-resistant and fistulating Crohn's disease. Although efficacy has been shown in clinical trials, financial implications often limit its use and limited data exist regarding clinical practice. AIMS: To audit the clinical effectiveness of Infliximab. METHODS: We prospectively audited 50 consecutive patients [28 females; median age, 34 years (17-70 years)]. Disease activity and response rates were assessed by the Harvey-Bradshaw index. Clinical and disease data were collected and blood was taken for inflammatory markers, complement and double-stranded DNA antibodies. Patients received Infliximab at 5 mg/kg and were followed for 12 weeks. RESULTS: Indications for Infliximab were refractory Crohn's disease in 39 patients, fistulating Crohn's disease in six, pyoderma gangrenosum in one, pouchitis in two and coeliac disease in two. Thirty-one (79%) of the refractory Crohn's disease patients and four (66%) of the fistulating patients responded at 4 weeks. Twenty-one (54%) of the refractory Crohn's disease patients had a continued response at 12 weeks. Perianal disease was more prevalent in non-responders (7/8 vs. 12/31, P < 0.02). CONCLUSIONS: Response rates to Infliximab in our group are comparable to those of clinical trials. Despite the expense, it remains a useful adjunct to treatment in this otherwise difficult group of patients. Patients with perianal disease responded less well in our cohort.

Portal hypertension in the presence of minimal liver damage in Crohn's disease on long-term azathioprine: possible endothelial cell injury.

Azathioprine is a useful agent for the treatment of Crohn's disease but side effects occur in 10% of patients. Hepatic toxicity is well recognized and is usually associated with abnormalities of liver function tests. We describe a female patient who was on azathioprine for the treatment of Crohn's disease for a total of 216 months. She developed portal hypertension complicated by variceal haemorrhage. This required the insertion of a trans-jugular intra-hepatic porto-systemic shunt to control the bleeding. Subsequent histology has shown mild nodular regenerative hyperplasia, and other causes of liver disease have been excluded. The only liver function abnormalities were mild elevation of bilirubin and a low albumin in the later stages.

The spectrum of ischaemic colitis.

OBJECTIVE: Ischaemic colitis is generally considered a disease of the elderly with considerable cardiovascular morbidity. We aimed to determine the effect of age, co-morbidity and clinical presentation on type, severity and anatomy of involvement of ischaemic colitis. Thrombophilic tendencies have been poorly studied and coagulation status was performed in available patients. DESIGN: Retrospective case identification with prospective follow-up. SETTING: University teaching hospital. PARTICIPANTS: Twenty-four patients (16 female, mean age 64 years) with ischaemic colitis. INTERVENTIONS: Blood analysis for clotting tendencies. MAIN OUTCOME MEASURES: Operation rates, death rates and frequency of clotting abnormalities. RESULTS: Five patients (21%) were below the age of 45, and seven of the 24 had died by the time of follow-up. Four had died of ischaemic colitis during the acute episode. The four patients that died of ischaemic colitis had a more extensive and more severe type of disease and presented with worse clinical features. The main predisposing factors were ischaemic heart disease in 12 (50%) and malignancy in five (21%). Six of the 24 cases (25%) had right-sided lesions and this conferred a good prognosis. Shock, peritonism, extensive disease and uncontrolled atrial fibrillation were all poor prognostic factors. Clotting factor abnormalities could be detected in three of nine patients despite a time lapse between assay and episode of ischaemic colitis. CONCLUSIONS: Ischaemic colitis appears to have two patterns of severity. Anatomical distribution is more variable than a developmental explanation of the vascular supply. Clotting abnormalities may be detected in a minority even on retrospective testing.

Gut luminal neutrophil migration is influenced by the anatomical site of Crohn's disease.

BACKGROUND: Clinical differences between small- and large-bowel Crohn's disease have been demonstrated. Neutrophil migration and degranulation are important effector mechanisms in gut damage. Granulocyte elastase, a neutrophil-bound enzyme, interleukin 8 and 1beta can be detected in whole-gut lavage fluid. We aimed to assess differences between large- and small-bowel Crohn's disease. METHODS: A total of 167 patients with active inflammatory bowel disease (118 Crohn's disease, 49 ulcerative colitis) underwent whole-gut lavage with a polyethylene glycol electrolyte solution. Granulocyte elastase was assayed using an enzyme substrate reaction, IL-8 and IL-1beta by ELISA. RESULTS: Twenty-seven of 36 patients with isolated colonic Crohn's disease had detectable granulocyte elastase (median 0.259 pKat/l, range < 0.039-2.742 microKat/l), whereas 3 of 15 with small-bowel involvement alone had detectable granulocyte elastase (median < 0.039 microKat/l, range < 0.039-0.266 microKat/l; P < 0.0001). Granulocyte elastase levels were significantly higher in patients with ileocolonic disease and post-ileocaecal resection compared with small-bowel disease alone. IL-8 (P< 0.0001) and IL-1beta (P < 0.04) levels differed between colonic and ileal distributions. No variations were seen in ulcerative colitis. CONCLUSIONS: Neutrophil migration to the gut lumen in Crohn's disease is a feature of colonic disease irrespective of associated ileal lesions. This suggests that bacterial-derived chemo-attractants may play a role. High levels of IL-8 in colonic disease are consistent with this hypothesis.

Whole gut lavage fluid interleukin-1beta and interleukin-8 in smokers and non-smokers with Crohn's disease in clinical remission.

INTRODUCTION: Smoking in patients with Crohn's disease is associated with more frequent relapse. The mechanism responsible is unknown but a direct pro-inflammatory action on intestinal mucosa has been postulated. Mucosal inflammation in clinically inactive Crohn's disease predicts forthcoming relapse. Whole gut lavage fluid obtained after bowel cleansing with a polyethylene glycol electrolyte solution is an assessment of gut inflammation and immunity. AIM: To assess whether whole gut lavage fluid interleukin-1beta and interleukin-8 differed between smokers and non-smokers with clinically inactive Crohn's disease. METHODS: A total of 34 patients with inactive Crohn's disease (Crohn's disease activity index <150 and whole gut lavage fluid IgG concentration of <10 mg/ml) underwent whole gut lavage with interleukin-1beta and interleukin-8 analysed by enzyme-linked immunosorbent assay. Clinical details and blood markers of inflammation were collected. RESULTS: In this series, 14 patients smoked (10 females, mean age 44.3+/-14.3 years), 20 did not (12 females, mean age 40.7+/-14.3). Surgical resection was more common in smokers (12/14 vs 8/20, p<0.008). Whole gut lavage fluid IgG was significantly lower in smokers (median 1.5 mg/ml (range 1.0-8.0 mg/ml) vs median 3.5 mg/ml (range 1.0-7.0 mg/ml), p<0.05). Whole gut lavage fluid interleukin-1beta was also lower in smokers [median 14.5 pg/ml (range 2-72 pg/ml) vs 26 pg/ml (range 7-1700 pg/ml)], p<0.03. CONCLUSION: Markers of mucosal inflammation in inactive Crohn's disease are lower in smokers than non-smokers. This is against the hypothesis that nicotine exerts a direct pro-inflammatory action via interleukin-1beta and interleukin-8. Further research is required to elucidate the exact mechanisms involved.

Whole gut lavage fluid analysis : a minimally invasive method for study of mucosal immunity and inflammation.

Studies of intestinal mucosal immunity and inflammation are limited by the relative inaccessibility of most of the small intestine. Any new method of studying mucosal immunity and inflammation in patients should be minimally invasive, cost-effective, and provide information not readily available using current methods. Gaspari et al. (1) described gut lavage with 3 to 4 L of nonabsorbable, commercially available polyethylene glycol (PEG)-based bowel cleansing fluid as a method for analyzing human intestinal secretions for antibody content. Peroral gastrointestinal (GI) lavage is widely used to cleanse the GI tract prior to colonoscopy, barium enema examination, or colonic surgery. Whole gut lavage fluid (WGLF) therefore often becomes available without subjecting a patient to any additional investigation. This method is also often more acceptable to healthy volunteers than almost any other method of studying small intestinal secretions. Over the past decade, we have found that WGLFs from patients (both adults and children) suffering from a variety of intestinal diseases contain immunoglobulins (Igs) and antibodies, hemoglobin, plasma-derived proteins, cytokines, inflammatory cells, and their granule-derived proteins and growth factors (2,3). In this chapter, we describe our experience of the use of WGLF to study mucosal immunity and inflammation.