Unique microbial-derived volatile organic compounds in portal venous circulation in murine non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease is now the leading liver disease in North America. The progression of non-alcoholic fatty liver disease to the inflammatory condition, non-alcoholic steatohepatitis is complex and currently not well understood. Intestinal microbial dysbiosis has been implicated in the development of non-alcoholic fatty liver disease and progression of non-alcoholic steatohepatitis. Volatile organic compounds are byproducts of microbial metabolism in the gut that may enter portal circulation and have hepatotoxic effects contributing to the pathogenesis of non-alcoholic steatohepatitis. To test this hypothesis, we measured volatile organic compounds in cecal luminal contents and portal venous blood in a mouse model of non-alcoholic steatohepatitis. METHODS: Gas chromatography-mass spectrometry analysis was conducted on cecal content and portal vein blood for volatile organic compound detection from mice fed a methionine and choline deficient diet, which induces non-alcoholic steatohepatitis. The colonic microbiome was studied by 16S rRNA gene amplification using the Illumina MiSeq platform. RESULTS: Sixty-eight volatile organic compounds were detected in cecal luminal content, a subset of which was also present in portal venous blood. Importantly, differences in portal venous volatile organic compounds were associated with diet-induced steatohepatitis establishing a biochemical link between gut microbiota-derived volatile organic compounds and increased susceptibility to non-alcoholic steatohepatitis. CONCLUSION: Our model creates a novel tool to further study the role of gut-derived volatile organic compounds in the pathogenesis of non-alcoholic steatohepatitis.

Use of risedronate to prevent bone loss following a single course of glucocorticoids: findings from a proof-of-concept study in inflammatory bowel disease.

SUMMARY: We performed a randomised controlled trial (RCT) to determine whether risedronate 35 mg once weekly prevents bone loss following an 8-week reducing course of prednisolone given for an exacerbation of inflammatory bowel disease (IBD). The greatest change in bone mineral density (BMD) was at Ward's triangle (WT), which fell by 2.2% in the placebo group, compared with a reduction of 0.8% in the risedronate group. INTRODUCTION: Whether bisphosphonates can prevent bone loss associated with intermittent glucocorticoid (GC) therapy is unknown, reflecting the difficulty in performing RCTs in this context. METHOD: To explore the feasibility of RCTs to examine this question, lumbar spine (LS; L2-4) and hip dual X-ray absorptiometry (DXA) scans were performed in 78 patients commencing a GC therapy course for a relapse of IBD. They were then randomised to receive placebo or risedronate 35 mg weekly for 8 weeks, after which the DXA scan was repeated. RESULTS: For LS BMD, there was no change in the placebo group (0.1 +/- 0.4, p = 0.9), but there was an increase after risedronate (0.8 +/- 0.4, p = 0.04; mean% +/- SEM by paired Student's t test). There were small decreases in both groups at the total hip (-0.5 +/- 0.3, p = 0.04; -0.5 +/- 0.3, p < 0.05, placebo and risedronate, respectively). At WT, BMD fell after placebo (-2.2 +/- 0.5, p = 0.001) but not risedronate (-0.8 +/- 0.5, p = 0.09; p = 0.05 for between-group comparison). CONCLUSION: RCTs can be used to examine whether bisphosphonates prevent bone loss associated with intermittent GC therapy, providing metabolically active sites such as WT are employed as the primary outcome.

Review article: steroid resistance in inflammatory bowel disease - mechanisms and therapeutic strategies.

BACKGROUND: Steroid resistance in inflammatory bowel disease presents a difficult clinical challenge. The advent of biological therapies coupled with an increasing understanding of the pathogenesis of inflammatory bowel disease has provided new therapeutic options. METHODS: We review the available literature of the mechanisms behind steroid resistance. In addition, we outline some of the options available for treating those patients who fail to respond adequately to glucocorticoids. RESULTS: Approximately 30% of patients prescribed glucocorticoids will not achieve clinical remission. Many such patients are offered immunosuppressive or, recently, biological agents. However, these agents are ineffective in a large proportion of patients. Immunosuppressive agents only bring 40-60% of patients into remission, and biological agents typically induce remission in just 40% of patients. In this review, the possible explanations for glucocorticoid resistance are discussed. Recent evidence suggests that in many patients it is mediated by interleukin-2. Basiliximab, a biological agent that interrupts interleukin-2 signalling, has shown significant benefit in early clinical studies. CONCLUSIONS: Patients who fail to respond to steroid therapy should have alternative agents introduced in a timely fashion. Steroid refractory inflammatory bowel disease remains a difficult condition to treat, but new therapies and managements are emerging.

A randomized, double-blind, placebo-controlled trial of lenalidomide in the treatment of moderately severe active Crohn's disease.

BACKGROUND: Therapy targeted at tumour necrosis factor-alpha has an established role in Crohn's disease. Lenalidomide, an analogue of thalidomide, is an oral immunomodulatory agent with powerful antitumour necrosis factor-alpha properties. It is licensed for myeloma and myelodysplastic syndrome. Based upon reports of thalidomide efficacy, lenalidomide was evaluated in Crohn's disease. AIM: To evaluate the efficacy and safety of lenalidomide in subjects with moderately severe active Crohn's disease. METHODS: In a multicentre, double-blind, placebo-controlled parallel group study 89 subjects were randomized to lenalidomide 25 mg daily, 5 mg daily or placebo. Subjects were treated for 12 weeks. The primary end point was a 70-point reduction in Crohn's Disease Activity Index. RESULTS: The overall clinical response rate was not significantly different between the three groups: lenalidomide 25 mg 26%, lenalidomide 5 mg 48% and placebo 39%. Lenalidomide was generally well tolerated with only one serious adverse event, a deep vein thrombosis, being attributed to treatment. CONCLUSION: Lenalidomide, an oral agent with antitumour necrosis factor-alpha properties, was not effective in active Crohn's disease in contrast to reports of benefit from thalidomide. The reasons for this lack of efficacy are speculative, other physiological activities may offset its action on inflammatory cytokines, or its antitumour necrosis factor-alpha action without apoptosis may be insufficient for activity in Crohn's disease.

Irritable bowel syndrome and active inflammatory bowel disease diagnosed by faecal gas analysis.

BACKGROUND: Inflammatory bowel disease and irritable bowel syndrome may present in a similar manner. Measuring faecal calprotectin concentration is often recommended to rule out inflammatory bowel disease, however, there are no tests to positively diagnose irritable bowel syndrome and invasive tests are still used to rule out other pathologies. AIM: To investigate a platform technology for diagnosing inflammatory bowel disease and irritable bowel syndrome based on faecal gas. METHODS: The platform technology is composed of a gas chromatography column coupled to a metal oxide gas sensor (OdoReader) and a computer algorithm. The OdoReader separates the volatile compounds from faecal gas and the computer algorithm identifies resistance patterns associated with specific medical conditions and builds classification models. This platform was applied to faecal samples from 152 patients: 33 patients with active inflammatory bowel disease; 50 patients with inactive inflammatory bowel disease; 28 patients with irritable bowel syndrome and 41 healthy donors (Control). RESULTS: The platform classified samples with accuracies from 75% to 100% using rigorous validation schemes: namely leave-one-out cross-validation, 10-fold cross-validation, double cross-validation and their Monte Carlo variations. The most clinically important findings, after double cross-validation, were the accuracy of active Crohn's disease vs. irritable bowel syndrome (87%; CI 84-89%) and irritable bowel syndrome vs. controls (78%; CI 76-80%). These schemes provide an estimate of out-of-sample predictive accuracy for similar populations. CONCLUSIONS: This is the first description of an investigation for the positive diagnosis of irritable bowel syndrome, and for diagnosing inflammatory bowel disease.

Review article: maintenance therapy in patients with ulcerative colitis.

British Society of Gastroenterology guidelines recommend that all patients with ulcerative colitis should receive long-term therapy with a 5-aminosalicylic acid compound to maintain remission. Recent studies have shown that time spent in remission is longer when the maintenance dose is increased from 1.2 to 2.4 g/day, with patients with extensive disease benefiting most from an increase with dosage. A retrospective analysis also found that the frequency of relapse was lower in patients taking more than the median dose of 5-aminosalicylic acid (1.6 g/day) compared with those taking less than the median dose. Similarly, when 5-aminosalicylic acids are used to induce remission, continuing the induction dosage for an extra 4 weeks prolongs remission and reduces the frequency of relapse. However, patients rarely comply fully with the prescribed dose regimen, which can lead to effective under-dosing. The recent discovery that 5-aminosalicylic acids may act in ulcerative colitis by activating peroxisome proliferator-activated receptor-gamma, a nuclear receptor that plays a role in the control of cell proliferation and apoptosis, has given new impetus to the idea that long-term therapy with 5-aminosalicylic acid may reduce the risk of colorectal cancer. Epidemiological studies are beginning to provide evidence to support this view. Accumulating evidence suggests that the next revision of the clinical guidelines should suggest life-long doses of 5-aminosalicylic acid of > or =2 g/day for maintenance of remission in patients with ulcerative colitis.

Basiliximab for the treatment of steroid-resistant ulcerative colitis: further experience in moderate and severe disease.

BACKGROUND: Preliminary data have suggested that interleukin-2 receptor blockade with basiliximab may increase steroid sensitivity. We have previously reported a small case series demonstrating the potential of basiliximab as a novel agent for the treatment of steroid-resistant ulcerative colitis. AIM: To report further experience of the efficacy and safety of treatment with the interleukin-2 receptor blocking monoclonal antibody basiliximab, in addition to steroids, for the treatment of severe and moderate steroid-resistant ulcerative colitis. METHODS: Twenty patients were enrolled - 13 patients with moderate steroid-resistant ulcerative colitis (Ulcerative Colitis Symptom Score: >or=6) and seven patients with severe steroid-resistant ulcerative colitis. All were given a single dose of 40 mg basiliximab plus standard steroid therapy in an open-label, uncontrolled trial. Primary end point was clinical remission within 8 weeks (Ulcerative Colitis Symptom Score:

Investigation of faecal volatile organic metabolites as novel diagnostic biomarkers in inflammatory bowel disease.

BACKGROUND: The aetiology of inflammatory bowel disease (IBD) remains poorly understood. Recent evidence suggests an important role of gut microbial dysbiosis in IBD, and this may be associated with changes in faecal volatile organic metabolites (VOMs). AIM: To describe the changes in the faecal VOMs of patients with IBD and establish their diagnostic potential as non-invasive biomarkers. METHODS: Faecal samples were obtained from 117 people with Crohn's disease (CD), 100 with ulcerative colitis (UC), and 109 healthy controls. Faecal VOMs were extracted using solid-phase micro-extraction and analysed by gas chromatography mass spectrometry. Data analysis was carried out using partial least squares-discriminate analysis (PLS-DA) to determine class membership based on distinct metabolomic profiles. RESULTS: The PLS-DA model showed clear separation of active CD from inactive disease and healthy controls (P < 0.001). Heptanal, 1-octen-3-ol, 2-piperidinone and 6-methyl-2-heptanone were up-regulated in the active CD group [variable important in projection (VIP) score 2.8, 2.7, 2.6 and 2.4, respectively], while methanethiol, 3-methyl-phenol, short-chain fatty acids and ester derivatives were found to be less abundant (VIP score of 3.5, 2.6, 1.5 and 1.2, respectively). The PLS-DA model also separated patients with small bowel CD from healthy controls and those with colonic CD from UC (P < 0.001). In contrast, less distinct separation was observed between active UC, inactive UC and healthy controls. CONCLUSIONS: Analysis of faecal volatile organic metabolites can provide an understanding of gut metabolomic changes in IBD. It has the potential to provide a non-invasive means of diagnosing IBD, and can differentiate between UC and CD.

Review article: cytomegalovirus and inflammatory bowel disease.

BACKGROUND: The association between ulcerative colitis and cytomegalovirus (CMV) has been recognised for over 50 years; and the role of CMV in ulcerative colitis in general, and steroid resistance in particular, remains a topic of ongoing controversy. The outcome for patients with CMV reactivation appears worse than that for patients without reactivation, but it is not entirely clear whether CMV is a contributor or a bystander and if treatment with anti-virals alters the course of inflammatory bowel disease (IBD). AIM: To review the role of CMV associated with IBD, including epidemiology, clinical features, diagnosis and management strategies. METHODS: By reviewing literature available on CMV associated with IBD in adult patients. A PubMed literature search was performed using the following terms individually or in combination: CMV colitis, cytomegalovirus colitis, IBD and CMV, CMV treatment. RESULTS: Cytomegalovirus reactivation is common in patients with severe colitis, with a reported prevalence of 4.5-16.6%, and as high as 25% in patients requiring colectomy for severe colitis. The outcome for this group of patients appears worse than that for patients without reactivation; however, reported remission rates following treatment with anti-viral therapy are as high as 71-86%. CONCLUSIONS: Evidence, although not conclusive, supports testing for CMV colonic disease in cases of moderate to severe colitis, by processing biopsies for haematoxylin and eosin staining with immunohistochemistry and/or, CMV DNA real-time polymerase chain reaction; and if present treating with ganciclovir.

Mucins in the gastrointestinal tract in health and disease.

Mucins form part of the dynamic, interactive mucosal defensive system active at the mucosal surface of the gastrointestinal tract. They are carbohydrate rich glycoproteins with unique molecular structure and chemical properties. The family of mucin (MUC) genes has 13 members that can be divided into secreted and membrane-associated forms each with characteristic protein domains and tissue specific glycosylation. Biosynthetic pathways have been described for the secreted and membrane-associated mucins and their eventual degradation and turnover. Mucins are present at all mucosal surfaces throughout the body in typical combinations and relate to the demands of organ function. Patterns of MUC gene expression with gastrointestinal site specific glycosylation are clearly important but are not yet well defined. Mucin production during fetal development shows distinct patterns that may correlate in many cases with neoplastic expression in adult life. An increasing number of protective proteins have been identified that appear in the adherent mucus layer at the mucosal surface. These proteins are co-secreted with mucins in some cases, interact with mucins at a molecular level through peptide and carbohydrate sites or benefit from the viscoelastic, aqueous environment afforded by the mucus gel to effect their defensive roles. The mechanism of many of these interaction remains to be elucidated but is clearly part of an integrated innate and adaptive mucosal defensive system relying on the mucins as an integral component to provide a mucus gel. Recent improvements in the description of MUC gene expression and mature mucin synthesis in the healthy gastrointestinal tract has formed a basis for assessment of mucosal disease at sites throughout the tract. Pathological patterns of mucin expression in disease appear to follow tissue phenotype, so that gastric and intestinal types can be defined and appear in metaplasia in e.g. esophagus and stomach. Adaptation of previous mucin based, histochemical classification of intestinal metaplasia to assess MUC gene expression has proved helpful and promises greater value if reliably combined with mucin linked glycosylation markers. Few changes in MUC gene expression or polymorphism have been detected in inflammatory bowel diseases in contrast to malignant transformation. Glycosylation changes however, are evident in both types of disease and appear to be early events in disease pathogenesis. Review of the major mucosal diseases affecting the gastrointestinal tract in childhood reveals parallel patterns to those found in adult pathology, but with some novel conditions arising through the developmental stages at lactation and weaning. The impact of bacterial colonization and nutrition at these stages of life are important in the evaluation of mucosal responses in pediatric disease.

An investigation of the association of the prothrombin G20210A gene mutation and inflammatory bowel disease: Factor II and IBD.

BACKGROUND: A thrombotic etiology for inflammatory bowel disease (IBD) has been proposed as a result of its association with thromboembolic complications, smoking, the oral contraceptive pill, and the response of ulcerative colitis (UC) patients to heparin. We have previously demonstrated an increased prevalence of the Factor V Leiden mutation in UC and wished to investigate the frequency of the recently discovered prothrombin G20210A gene mutation in IBD. The aim of the study was to investigate the hypothesis that the prothrombic state associated with the prothrombin G20210A gene mutation is involved in the etiology of IBD. PATIENTS AND METHODS: A prospective cohort study of patients attending the Bristol Royal Infirmary and Gloucestershire Royal Hospital's IBD clinics was performed. Thirty-nine patients with IBD (24 with Crohn's disease and 15 with UC) and 100 historical controls were screened for the presence of the prothrombin gene mutation using a heteroduplex-based polymerase chain reaction technique. None of the patients with IBD had a personal history of thromboembolism, while three of them had a family history. RESULTS: No IBD patients had the prothrombin gene mutation compared with four (4%) controls (allelic frequency 2%). CONCLUSION: There does not appear to be an association of the prothrombin gene mutation with IBD and therefore it is unlikely to be involved in the etiology of IBD.

Rapid hip bone loss in active Crohn's disease patients receiving short-term corticosteroid therapy.

BACKGROUND: Uncertainty over whether corticosteroids cause bone loss in patients with Crohn's disease may reflect their short, intermittent use. AIM: We investigated whether a 2-month course of prednisolone is associated with detectable bone loss. METHODS: Fifteen patients with active Crohn's disease and 19 controls with inactive Crohn's disease were recruited. Bone mineral density of the lumbar spine and hip was measured at baseline and 2 and 8 months. RESULTS: At 2 months, significant bone loss was found in patients with active disease (femoral neck -2.7%, P < 0.002; Ward's triangle -3.9%, P < 0.01). Although bone mineral density was still lower at 8 months, these differences were no longer significant (-1.3% and -3.4%, femoral neck and Ward's triangle, respectively). No significant change in hip bone mineral density was observed in controls. Previous corticosteroid use was not significantly associated with baseline bone mineral density, although significant independent associations were observed between weight, site of disease and lumbar spine bone mineral density, and between dietary calcium deficiency and femoral neck and Ward's triangle bone mineral density. CONCLUSION: Significant bone loss at the hip can be detected in patients receiving corticosteroid treatment for 2 months for active Crohn's disease ; however, it remains unclear whether this is because of disease activity or its treatment. This rapid bone loss may represent a risk factor for fracture and justify bone protective therapy.

Is your patient taking the medicine? A simple assay to measure compliance with 5-aminosalicylic acid-containing compounds.

BACKGROUND: Poor compliance with 5-aminosalicylic acid therapy has been reported amongst patients with inflammatory bowel disease. Currently, there is no easy method to monitor 5-aminosalicylic acid; however, the chemical similarity between 5-aminosalicylic acid and salicylate might provide a solution. AIM: To determine the feasibility of using salicylate levels to monitor compliance with 5-aminosalicylic acid medication. METHODS: Thirty-six patients with inflammatory bowel disease, taking maintenance 5-aminosalicylic acid, provided either a paired serum and urine sample or an intestinal biopsy. Samples were split into two: half were sent to the hospital biochemistry department for salicylate measurement, and half were analysed for 5-aminosalicylic acid and its metabolite, N-acetyl-5-aminosalicylic acid, using high performance liquid chromatography. Correlation between the results was calculated. RESULTS: Serum and urine were available for 25 patients. Serum salicylate was undetectable, but urinary salicylate ranged from 31 to 3254 microg/mL. The correlations between urinary salicylate and 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid were 0.96 (95% confidence interval, 0.91-0.98) and 0.9 (95% confidence interval, 0.77-0.96), respectively. Sixteen biopsies were available from 13 patients. The 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid concentrations were 0.2-657 ng/mg and 1.6-1598 ng/mg, respectively; there was no correlation with bowel salicylate. CONCLUSIONS: The close correlation between 5-aminosalicylic acid and salicylate levels offers a simple method to assess compliance with 5-aminosalicylic acid therapy.

Refeeding syndrome: effective and safe treatment with Phosphates Polyfusor.

BACKGROUND: Severe hypophosphataemia associated with refeeding syndrome requires treatment with intravenous phosphate to prevent potentially life-threatening complications. However, evidence for replacement regimens is limited and current regimens are complex and replace phosphate inadequately. AIM: To assess the effectiveness and safety of 50 mmol intravenous phosphate infusion, given as a 'Phosphates Polyfusor', for the treatment of severe hypophosphataemia in refeeding syndrome. METHODS: Patients with refeeding syndrome and normal renal function received a Phosphates Polyfusor infusion for the treatment of severe hypophosphataemia (< 0.50 mmol/L). The outcome measures were serial serum phosphate, creatinine and calcium concentrations for 4 days following phosphate infusion and adverse events. RESULTS: Over 2 years, 30 patients were treated. Following treatment, 37% of cases had a normal serum phosphate concentration and 73% had a serum phosphate concentration of > 0.5 mmol/L within 24 h. Ten patients required more than one Phosphates Polyfusor infusion. Within 72 h, 93% of cases had achieved a serum phosphate concentration of > or = 0.50 mmol/L. No patient developed renal failure. Three episodes of transient mild hyperphosphataemia were recorded. Four patients developed mild hypocalcaemia. CONCLUSIONS: This is the largest published series of the use of intravenous phosphate for the treatment of severe hypophosphataemia (< 0.50 mmol/L), and is the most effective regimen described. All patients had refeeding syndrome and were managed on general wards.

Basiliximab (anti-CD25) in combination with steroids may be an effective new treatment for steroid-resistant ulcerative colitis.

BACKGROUND: Steroid resistance represents a major clinical problem in the treatment of ulcerative colitis. In vitro, interleukin-2 renders lymphocytes steroid resistant. AIM: To explore the therapeutic potential of interleukin-2 receptor blockade in steroid-resistant ulcerative colitis with both in vitro measures and a pilot in vivo study. METHODS: Ten patients with steroid-resistant ulcerative colitis received a single bolus of 40 mg of intravenous basiliximab plus steroid treatment in an open-label, uncontrolled, 24-week study. The outcome was assessed using the Ulcerative Colitis Symptom Score, rectal biopsy and Inflammatory Bowel Disease Questionnaire. Lymphocyte steroid sensitivity was measured in vitro in 39 subjects in the presence or absence of basiliximab. RESULTS: Nine of the 10 patients achieved clinical remission within 8 weeks. At 24 weeks, seven patients were in clinical remission. Marked improvement in the Ulcerative Colitis Symptom Score was seen by 1 week (P = 0.004) and on rectal biopsy and Inflammatory Bowel Disease Questionnaire by 2 weeks (both P < 0.05). Improvements persisted to 24 weeks (Ulcerative Colitis Symptom Score, Inflammatory Bowel Disease Questionnaire, both P < 0.005). Eight of the nine responders relapsed (median, 9 weeks), but remission was re-achieved with further corticosteroids and the addition of azathioprine. At 24 weeks, seven patients were in full clinical remission, five off all steroid therapy. In vitro measurement of lymphocyte steroid sensitivity demonstrated steroid resistance in 22% of subjects. All were rendered steroid sensitive in the presence of basiliximab. CONCLUSIONS: Basiliximab appears to be effective at inducing remission in steroid-resistant ulcerative colitis. In vitro, basiliximab also produced a dramatic increase in lymphocyte steroid sensitivity in healthy subjects. Confirmation in randomized controlled studies is required.

Some determinants of whole-gut transit time: a population-based study.

Slow whole-gut transit time may be associated with an increased risk of gallstones, and possibly bowel cancer, but its determinants are unknown. We looked for these determinants in a community-based study of 884 women aged 25-69 years and 677 men aged 40-69 years. Transit time was estimated using prospective examination of three stools and a questionnaire about bowel habit. Diet and alcohol intake were assessed using a validated food frequency questionnaire. In women < 50 years not taking oral contraceptives, mean transit time was relatively constant across 10-year age bands (62 to 63 h). In older women it was also relatively constant, but was significantly shorter (58 to 59 h), suggesting an effect of female sex hormones. In women taking oral contraceptives, mean transit-time was 6 h longer than in women of the same age not taking them (95% CI 1.4 to 10.6 h). In men drinking > 40 g alcohol/day, mean transit time was 49 h compared with 54 h in those drinking < 20 g/day (p < 0.0001). In alcohol-abstaining men, an effect of dietary NSP (non-starch polysaccharide or fibre) intake was clearly apparent. Alcohol consumption quickened transit in both sexes; oral contraceptive usage slowed it in women. Body mass index in both sexes, soluble NSP in men, and insoluble NSP in women also significantly and negatively affected transit time. The food groups which were related to transit time were potatoes and cooked fruit in men, and pulses and bread in women.(ABSTRACT TRUNCATED AT 250 WORDS)

Audit of cyclosporin use in inflammatory bowel disease: limited benefits, numerous side-effects.

BACKGROUND: The failure of standard treatments for inflammatory bowel disease (IBD) has led to the use of immuno-modulatory therapy. Most reports of the use of cyclosporin are from single specialist centres. AIM: To survey the use of cyclosporin in IBD in Bristol's three teaching hospitals. PATIENTS AND METHODS: Over a 4-year period, all patients receiving cyclosporin for IBD were identified and the following data recorded: diagnosis, duration of disease, initial treatment, date initiated, dose of cyclosporin, side-effects, initial clinical response, and current patient status. RESULTS: Thirty-three patients were identified, of whom 26 had ulcerative colitis (UC), six had Crohn's disease and one had indeterminant colitis. The most frequent indication was as 'rescue' therapy in acute severe UC. The overall initial response rate was 63%, but this was only maintained in 30% long-term patients, with over half of them reporting side-effects. Four patients had life threatening side-effects. CONCLUSION: Although the initial response rates are encouraging, the long-term results are poor and at the expense of a high incidence of side-effects. We feel that the use of cyclosporin in IBD should be reconsidered until more information from randomized controlled studies becomes available.

An investigation of the association of the factor V Leiden mutation and inflammatory bowel disease.

BACKGROUND: A thrombotic aetiology for inflammatory bowel disease (IBD) has been proposed as a result of its association with thrombo-embolic complications, smoking, the oral contraceptive pill and the response of ulcerative colitis (UC) patients to heparin. The factor V Leiden (FVL) mutation is the commonest inherited risk factor for thrombo-embolism. AIM: The aim of the study was to investigate the hypothesis that the pro-thrombotic state associated with the FVL mutation is involved in the aetiology of IBD. PATIENTS AND METHODS: A prospective cohort study of patients attending the Bristol Royal Infirmary IBD outpatient clinic was performed. Fifty-four patients with IBD (30 with Crohn's disease (CD) and 24 with UC) and 55 historical controls were screened for the presence of FVL using the activated protein C (APC) ratio. Abnormal APC ratios were confirmed to be due to FVL using a heteroduplex-based polymerase chain reaction (PCR) technique. RESULTS: Five patients had the FVL mutation, compared to two controls. One of the patients was homozygous. Two of the patients had CD and three UC. The differences between controls and IBD patients was significant when the allelic frequency of the FVL mutation in patients with UC was compared with controls, with a risk ratio of 2.27, but with limited data. CONCLUSION: There appears to be a weak association between FVL and UC. This association is not strong enough to imply a causal relationship, but may be responsible for some of the thrombo-embolic complications.