Outcome of adult patients receiving parenteral support at home: 36 years' experience at a tertiary referral centre.

BACKGROUND AND AIMS: Patients with intestinal failure often need long-term home parenteral support (PS). We aimed to determine how the underlying diagnosis, complications and survival had changed over the last 36 years in the UK's largest IF centre. METHODS: 978 adult home PS patient records were analysed from January 1979 until October 2016. The age, sex, underlying aetiology, complications and survival was compared over 5-year periods. RESULTS: Pre-1990 to 2011-2016, numbers increased from 29 to 451, the mean age of patients increased from 31 ± 16.5 to 52 ± 17.6 years. The percentage of patients with IF due to surgical complications increased (3.4%-28.8%, p < 0.001)), while those with inflammatory bowel disease decreased (37.9%-22.6%, p < 0.001). Complication of home PS reduced: catheter related blood stream infections (CRBSI) 71.4% to 42,2%, CVC thrombosis 34.5%-5.3%. Intestinal failure associated liver disease (IFLAD) 10.3%-1.8%. Patients with dysmotility, scleroderma and a congenital aetiology had the highest incidence of CRBSI and CVC Thrombosis. Overall survival was greater pre-1995 [HR 0.2-0.4 (p = 0.02)] most likely associated with an increase in mean age. Survival for patients without malignancy was 90%, 66%, 55%, 45%, 33% and 25% at 1,5, 10, 15, 20 and 30 years respectively. Multivariate analysis demonstrated a relationship between survival and age of starting home PS; type of home PS; presence or absence of the colon in continuity; and underlying aetiology. CONCLUSION: Demand for home PS is increasing in particular for advanced malignancy, post-surgical complications and older more co-morbid patients. Complications of home PS are reducing over the last 30 years and 10-year survival for non-malignant aetiologies improving. Survival and changes in aetiology in intestinal failure.

Enteral Autonomy and Days Off Parenteral Support With Teduglutide Treatment for Short Bowel Syndrome in the STEPS Trials.

BACKGROUND: Teduglutide response, in terms of parenteral support (PS) volume reduction, is associated with specific disease characteristics among adults with short bowel syndrome-associated intestinal failure (SBS-IF). Whether these associations apply to PS weaning with teduglutide is unknown. METHODS: Adults with SBS-IF treated with teduglutide in the phase III STEPS study and open-label extensions STEPS-2 and STEPS-3 were included in the analysis. Patients required PS ≥ 3 times weekly for ≥ 12 months at enrollment. The study population was stratified 3 times to create 3 distinct analysis populations based on bowel anatomy, etiology, and baseline PS volume. Outcomes included characteristics of patients who achieved PS independence and total and percentage of patients who had ≥ 1, ≥ 2, and ≥ 3 d/wk off PS at the end of STEPS, STEPS-2, and STEPS-3. RESULTS: Eight of 39 patients who received teduglutide in STEPS obtained PS independence during the STEPS study series. Patients required > 6 months of teduglutide treatment before enteral autonomy was achieved, regardless of underlying disease characteristics. Patients who attained PS independence and greater numbers of days per week off PS tended to have lower baseline PS volumes and noninflammatory bowel disease (non-IBD) etiology. Patients with ≥ 50% colon-in-continuity showed a trend for achieving greater numbers of days per week off PS. CONCLUSION: Although this analysis was limited by low patient numbers, results suggest that SBS-IF characteristics of lower baseline PS volume and non-IBD etiology were associated with PS reduction benefits with teduglutide in terms of days off per week and enteral autonomy.

Survival and CT defined sarcopenia in patients with intestinal failure on home parenteral support.

BACKGROUND & AIMS: Sarcopenia occurs in patients with intestinal failure (IF) and has been associated with poorer survival in several chronic diseases. CT can measure sarcopenia through a L3 skeletal muscle index (LSMI). We aim to describe the prevalence of sarcopenia in a section of our IF population using LSMI, & evaluate the effect of home parenteral support (PS) on LSMI & survival. Additionally, we aim to assess any association between LSMI, BMI & other anthropometric measurements. METHODS: IF patients on PS treated at St Mark's Hospital between 1/1/2006-1/10/2016 were identified from a prospectively maintained database. Patients were included if they were on PS & had 2 CTs: the first ≤30 days before start of HPN (pre-PS); the second ≥100 days from PS start (post-PS). Patient records were reviewed to obtain clinical & demographic information & date of death. Anthropometric measurements & BMI contemporaneous to CT scans were recorded. RESULTS: 64 patients met inclusion criteria (M:F 1:1). 83% of our cohort had LSMI below previously published thresholds for sarcopenia. Mean (SD) pre-PS LSMI was 36.5 (6.8)cm2/m2. Mean BMI pre-PS was 22.1 (4.8) kg/m2. Both BMI (22.1 kg/m2 to 23.5 kg/m2) p < 0.001) & LSMI (36.5 cm2/m2 to 38.4 cm2/m2) (p = 0.003) increased post-PS. A positive correlation was seen between BMI & LSMI pre (r = 0.47 p < 0.001) & post-PS (r = 0.37 p = 0.003). No correlation was seen between LSMI & anthropometric measurements pre-PS (p = 0.78) or post-PS (p = 0.96). 11 (17%) patients died during the study period; a low LSMI pre-PS was not a risk factor for mortality (HR 0.97 p = 0.55). CONCLUSIONS: This study is the first to look at sarcopenia & survival using CT defined LSMI (CT-LSMI) in the IF population. 83% of our cohort had a pre-PS LSMI below previously published thresholds, yet we found no relationship between lower baseline LSMI & survival. This may reflect the heterogeneity of the prognoses of the IF population, or that parenteral nutrition itself affects survival. Our study showed that LSMI & BMI improved following PS but demonstrated that other anthropometric measurements had poor correlation with LSMI & showed no significant improvement overall after PS, confirming the known problems of inter-operator & patient variability of these measurements. Whilst we found significant correlation between LSMI & BMI, BMI significantly underestimated the presence & degree of sarcopenia. LSMI has the potential to provide an objective & reproducible measure of sarcopenia in IF. Future larger studies should be performed to evaluate associations with patient outcomes & utility in clinical decision making.

Citrulline correlations in short bowel syndrome-intestinal failure by patient stratification: Analysis of 24 weeks of teduglutide treatment from a randomized controlled study.

BACKGROUND & AIMS: Disease-associated factors influence parenteral support (PS) reduction in response to teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS-IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume. METHODS: A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of teduglutide in patients with SBS-IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS-IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences. RESULTS: Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = -0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P < 0.0001), and an inverse correlation between change from baseline in citrulline and PS volume from baseline to Week 24 (r = -0.359, P = 0.001). In all subgroups, patients treated with teduglutide showed numerically greater increases in plasma citrulline at Week 24 compared with placebo. CONCLUSION: Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS-IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS-IF. ClinicalTrials.gov NCT00798967, ClinicalTrialsRegister.eu 2008-006193-15.

Factors Associated With Response to Teduglutide in Patients With Short-Bowel Syndrome and Intestinal Failure.

BACKGROUND & AIMS: Clinical studies showed teduglutide to increase urine production and reduce need for parenteral support volume in patients with short bowel syndrome (SBS) with intestinal failure, increasing intestinal wet weight absorption and reducing diarrhea. However, the effects of teduglutide on parenteral support vary among patients. We performed a post hoc analysis of a phase III placebo-controlled study to identify characteristics of patients in whom teduglutide has the largest effects on parenteral support volume response. METHODS: We collected data from 85 patients with SBS with intestinal failure, according to the European Society for Clinical Nutrition and Metabolism classification system, who received teduglutide or placebo between November 25, 2008, and January 4, 2011, at 27 sites in 10 countries. Changes in parenteral support volume were evaluated according to baseline parenteral support volume, bowel anatomy (group 1, jejunostomy/ileostomy; group 2, ≥50% colon-in-continuity without stoma; and group 3, other colon anatomies), and disease features (with inflammatory bowel disease, mesenteric vascular diseases, or other conditions). Correlation analyses were conducted using simple linear regression models, with unadjusted r2 values reported. Two-sided t tests were used for comparisons between treatment groups. RESULTS: We correlated parenteral support volume reduction with teduglutide treatment and baseline parenteral support volume (y = -0.3870x + 90.0279, r2 = 0.61; P < .0001). The effects of teduglutide on absolute parenteral support volume were significantly greater in group 1 patients (reduction of 919 ± 644 mL/d), not only compared with patients given placebo (reduction of 340 ± 436 mL/d; P = .0112) but also compared with teduglutide-treated patients in group 2 (reduction of 355 ± 306 mL/d; P = .0066). Teduglutide had an intermediate effect on patients in group 3. A minority of patients with SBS and inflammatory bowel diseases had colon-in-continuity (10.5% [n = 2/19]), whereas most patients with SBS and vascular or other diseases had colon-in-continuity (84.4% [n = 27/32] and 67.6% [n = 23/34], respectively). CONCLUSIONS: In a post hoc analysis of data from a phase III study of the effects of teduglutide on patients with SBS, we associated reduced parenteral support volume with baseline parenteral support volume, bowel anatomy, and SBS features. These findings may inform initial parenteral support volume adjustments and management of these severely disabled patients. ClinicalTrials.gov no: NCT00798967; ClinicalTrialsRegister.eu no: 2008-006193-15.

Pilot study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas.

BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a cytokine elevated in inflammatory bowel disease enterocutaneous fistula (IBD ECF). Dendritic cells are antigen presenting cells that orchestrate the immune responses and regulate the production of cytokines by immune cells including T cells. No study to date has assessed the level of TNF-α or the presence of dendritic cells in non-IBD ECF. The aim of this study was to assess the inflammatory activity, with a particular emphasis on TNF-α in non-IBD ECF when compared with control small bowel tissue. METHODS: Tissue biopsies were obtained from ECF at operation from non-IBD patients and from terminal ileum in normal colonoscopy control patients. After overnight culture, accumulation of intracellular TNF-α was measured by flow cytometry in cells treated with monensin to assess the on-going cytokine production. Data were acquired using FACS Canto II. Unpaired Student's t-test was used to compare variables between groups and p < 0.05 was regarded as significant. RESULTS: The on-going production of TNF-α from dendritic cells (p = 0.0007), putative monocyte and B cell populations (p = 0.04) and CD3+ T cells (p = 0.04) was significantly higher in non-IBD ECF tissue than that from control tissue. CONCLUSIONS: This study reveals results which provide evidence for the potential use of anti-TNF-α agents in the treatment of non-IBD ECF. A pilot study to evaluate this treatment as an alternative option in an already surgically challenging group of patients is planned. Positive findings would be a major medical advance with a new use for anti-TNF-α agents.

Growth factors and their use in short bowel.

PURPOSE OF REVIEW: To examine the most recent literature on the clinical trials associated with the relevant growth factors that have been of interest in the treatment of short bowel. RECENT FINDINGS: Short bowel is a rare but devastating condition that condemns patients to lifelong parenteral support. Historically, treatment options negating the need for parenteral support were limited. Therapeutic growth factor use is of interest, but the clinical trial data are inconclusive. The STEPS-2 trial was the first trial that showed a sustained positive effect of the growth factor glucagon-like peptide-2 (GLP-2). This led to a phase shift in the management of short bowel, with the US Food and Drug Administration approval of the GLP-2 analogue teduglutide in 2012. This review summarizes all the relevant clinical trials of growth factors in the treatment of short bowel. SUMMARY: GLP-2 has shown that growth factors can revolutionize the treatment of short bowel. Data however are lacking with regards to the solitary use of other factors. This review highlights the need for further work using the factors in combination as well as considering their use in novel methods for example in the field of regenerative medicine.

Spinal Infections Among Patients With Long-Term Central Venous Catheters for Home Parenteral Nutrition: A Descriptive Case Series.

Spinal infections are a rare yet serious metastatic complication of bacteremia among patients with long-term central venous catheters (CVCs) for which clinicians must remain vigilant. We performed a retrospective review of all cases of spinal infection occurring in the context of a CVC for long-term parenteral nutrition (PN) managed in our department between January 2010 and October 2013, a cohort of 310 patients over this time period. Six patients were identified (mean age, 65 years; 5 male). One hundred percent of patients presented with spinal pain (5/6 cervical, 1/6 thoracic). Organisms were cultured from the CVC in 5 of 6 patients. In all cases, the white blood cell count was normal, and in 5 of 6, C-reactive protein was normal. All diagnoses were confirmed on magnetic resonance imaging (MRI), and in 3 of 6 cases, an MRI was repeated (on the advice of neurosurgical colleagues) to confirm resolution of changes after a period of antimicrobial therapy. There was no clear correlation between duration of PN or number of days following CVC insertion and onset of infection. The CVC was replaced in 4 of 6 patients at the time of diagnosis, delayed removal in 1 of 6, and salvaged in the remaining case. Although rare, a high index of suspicion is needed in patients receiving long-term PN who present with spinal pain. Peripheral inflammatory markers may not be elevated. MRI should be performed and patients should be treated with antibiotics alongside involvement of local microbiology and neurosurgical teams. Multidisciplinary discussion on CVC salvage in these cases is important, especially in cases of challenging vascular anatomy.

Spinal Infections Among Patients With Long-Term Central Venous Catheters for Home Parenteral Nutrition.

Spinal infections are a rare yet serious metastatic complication of bacteremia among patients with long-term central venous catheters (CVCs) for which clinicians must remain vigilant. We performed a retrospective review of all cases of spinal infection occurring in the context of a CVC for long-term parenteral nutrition (PN) managed in our department between January 2010 and October 2013, a cohort of 310 patients over this time period. Six patients were identified (mean age, 65 years; 5 male). One hundred percent of patients presented with spinal pain (5/6 cervical, 1/6 thoracic). Organisms were cultured from the CVC in 5 of 6 patients. In all cases, the white blood cell count was normal, and in 5 of 6, C-reactive protein was normal. All diagnoses were confirmed on magnetic resonance imaging (MRI), and in 3 of 6 cases, an MRI was repeated (on the advice of neurosurgical colleagues) to confirm resolution of changes after a period of antimicrobial therapy. There was no clear correlation between duration of PN or number of days following CVC insertion and onset of infection. The CVC was replaced in 4 of 6 patients at the time of diagnosis, delayed removal in 1 of 6, and salvaged in the remaining case. Although rare, a high index of suspicion is needed in patients receiving long-term PN who present with spinal pain. Peripheral inflammatory markers may not be elevated. MRI should be performed and patients should be treated with antibiotics alongside involvement of local microbiology and neurosurgical teams. Multidisciplinary discussion on CVC salvage in these cases is important, especially in cases of challenging vascular anatomy.

Biocompatibility and potential of decellularized porcine small intestine to support cellular attachment and growth.

The aim of this study was to decellularize a 30 cm long segment of porcine small intestine, determine its in vivo behaviour and assess the type of immunological reaction it induces in a quantitative manner. A segment of porcine ileum up to 30 cm long, together with its attached vasculature, was decellularized via its mesenteric arcade as a single entity. The quality of the acellular scaffold was assessed histologically and using molecular tools. The host response to the scaffold was evaluated in a rodent model. Stereological techniques were incorporated into quantitative analysis of the phenotype of the macrophages infiltrating the scaffold in vivo. Lengths of ileal scaffold, together with its attached vasculature, were successfully decellularized, with no evidence of intact cells and DNA or collagen and GAGs overdegradation. Analysis of explants harvested over 2 months postimplantation revealed full-thickness recellularization and no signs of foreign body or immune reactions. Macrophage profiling proved that between weeks 4 and 8 in vivo there was a switch from an M1 (pro-inflammatory) to an M2 (pro-remodelling) type of response. We show here that the decellularization process results in a biocompatible and non-toxic matrix that upon implantation triggers cellular infiltration and angiogenesis, primarily characterized by a pro-remodelling type of mononuclear response, without inducing foreign body reaction or fibrosis.

Mesenteric Infarction: Clinical Outcomes After Restoration of Bowel Continuity.

INTRODUCTION: Patients who have a bowel resection for mesenteric infarction may require parenteral nutrition (PN). This study primarily aimed to determine the aetiological factors for a mesenteric infarction and the effects of restoring bowel continuity on the long-term PN requirements. METHODS: A retrospective review of data on patients treated for mesenteric infarction from 2000 to 2010. RESULTS: A total of 113 patients (61 women, median age 54 years) were identified. Seventy-four (65%) had a superior mesenteric artery thromboembolism, 25 (22%) had a superior mesenteric vein thrombosis, and 4 (3%) had superior mesenteric artery stricture or spasm. Patients younger than 60 years most commonly had a clotting abnormality (n = 23/46, 50%), whereas older patients had a cardiological risk factor (n = 11/17, 65%). All patients with a jejunostomy required long-term PN. Fifty-seven (49%) patients had restoration of bowel continuity (colon brought into circuit). After this, PN was stopped within 1 year in 20 (35%), within 2 years in 29 (50%) patients and within 5 years in 44 (77%) patients (P = 0.001). CONCLUSIONS: A thrombotic tendency is the main etiological factor in most patients younger than 60 years. An anastomosis of the remaining jejunum to the colon can allow PN to be stopped.

Predictors for developing intestinal failure in patients with Crohn's disease.

BACKGROUND AND AIM: Intestinal failure (IF) is a rare but devastating complication of Crohn's disease (CD). The clinical and surgical factors that predispose to IF are poorly understood. The aim of this study was to define clinical factors that predispose to IF. METHODS: A retrospective case-control study was performed using consecutive CD patients with IF who were identified from a prospective database. Local population-based controls were selected with which to compare demographic, phenotypic, and clinical outcomes. RESULTS: Eighty-two CD patients requiring long-term intravenous fluids or nutrition were studied. Diagnosis at age 16 years or less (P = 0.01) and a family history of inflammatory bowel disease (P = 0.02) were associated with a significantly higher risk for developing IF. Among the IF group, 53% had perioperative complications from intestinal resections contributing to long-term IF. Furthermore, these patients had more abdominal surgeries (P = 0.05) and stricturing disease was less common than in patients with primary active CD (P = 0.01). IF due to primary active CD was associated with penetrating behavior (P = 0.02) and early age at first surgery (P = 0.004). The need for intravenous nutrition as opposed to intravenous fluids correlated inversely with small intestine length (P < 0.001). CONCLUSIONS: CD resulting in IF relates to earlier age at diagnosis, family history of inflammatory bowel disease, stricturing disease, younger age at first surgery, and operative complications. These factors deserve consideration when planning therapy for CD patients.

A meta-analysis of outcomes following use of somatostatin and its analogues for the management of enterocutaneous fistulas.

OBJECTIVE: Several randomized control trials (RCTs) have compared somatostatin and its analogues versus a control group in patients with enterocutaneous fistulas (ECF). This study meta-analyzes the literature and establishes whether it shows a beneficial effect on ECF closure. METHODS: We searched MEDLINE, EMBASE, CINAHL, Cochrane, and PubMed databases according to PRISMA guidelines. Seventy-nine articles were screened. Nine RCTs met the inclusion criteria. Statistical analyses were performed using Review Manager 5.1. RESULTS: Somatostatin analogues versus control. Number of fistula closed: A significant number of ECF closed in the somatostatin analogue group compared to control group, P = 0.002.Time to closure: ECF closed significantly faster with somatostatin analogues compared to controls, P < 0.0001.Mortality: No significant difference between somatostatin analogues and controls, P = 0.68.Somatostatin versus control. Number of fistula closed: A significant number of ECF closed with somatostatin as compared to control, P = 0.04.Time to closure: ECF closed significantly faster with somatostatin than controls, P < 0.00001.Mortality: No significant difference between somatostatin and controls, P = 0.63 CONCLUSIONS: Somatostatin and octreotide increase the likelihood of fistula closure. Both are beneficial in reducing the time to fistula closure. Neither has an effect on mortality. The risk ratio (RR) for somatostatin was higher than the RR for analogues. This may suggest that somatostatin could be better than analogues in relation to the number of fistulas closed and time to closure. Further studies are required to corroborate these apparent findings.

A dangerous combination of binge and purge.

We present a 36-year-old female diagnosed with Crohn's disease at the age of 11 years. In 2001, she underwent a total colectomy and further small bowel resection as a result of active Crohn's. Her residual anatomy consisted of 150 cm of small bowel to an end jejunostomy. Subsequently, she developed short bowel syndrome with recurrent episodes of hypomagnesaemia, hypocalcaemia, and hypokalaemia. Dietetic assessment revealed her to be severely underweight at 37 kg with a bodymass index (BMI) of 14.4 kg/m(2) . During her admission, our patient underwent psychiatric assessment and was established on home parenteral nutrition (HPN). At the time of discharge, 1 month later, her weight had increased to 44 kg (BMI = 17.7 kg/m(2) ). Over the following 12-month period, she lost weight (BMI, 15.4 mg/m(2) ; weight, 39.5 kg) and she described a high stoma output (up to 17 L) and dehydration. Assessment of her oral intake found she was consuming an estimated 14,000 kcal and 600 g protein per day. At this time, the possibility of a new form of eating disorder was discussed with the patient and she agreed that her behavior i.e., using her stoma as a purging device, fulfilled the criteria for a diagnosis of bulimia nervosa and she was referred to a specialist eating disorder unit.

Emerging treatment options for short bowel syndrome: potential role of teduglutide.

INTRODUCTION: Current medical management of short bowel syndrome (SBS) involves the use of lifelong parenteral nutrition (PN). Glucagon-like peptide-2 (GLP-2), an important intestinotrophic growth factor has been shown to increase intestinal absorption in SBS through augmentation of post-resection intestinal adaptation. This may lead to the reduction of PN dependence in patients with SBS. AREAS COVERED IN REVIEW: Advancing research of GLP-2 physiology has spurred the growing understanding of the diverse effects of GLP-2. The development of the degradation resistant GLP-2 analog, teduglutide (Gattex(TM), NPS Pharmaceuticals, Bedminster, NJ), has allowed its exploration as a therapeutic agent in a variety of clinical settings. Recent multicenter, placebo-controlled studies of GLP-2 in SBS patients demonstrate meaningful reductions in PN requirements with good safety profiles. The reparative and immunomodulatory effects of teduglutide may also be beneficial in patients with inflammatory bowel disease (IBD). Safety concerns about possible carcinogenic properties during long-term use require ongoing evaluation. SUMMARY: GLP-2 appears to offer a novel adjuvant treatment modality for SBS. Promise for its use in other clinical settings like IBD has been shown in small pilot studies.

Prospective study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas.

BACKGROUND: Enterocutaneous fistulas (ECF) are debilitating and usually result following complex abdominal surgery. While there is an association with inflammatory bowel disease (IBD), a large number of fistulas occur after surgery not related to IBD. The consequences of ECF include short bowel syndrome and the need for long term parenteral nutrition.ECF can heal spontaneously and in the case of IBD can be cured by medical therapy in some instances. Those that do not resolve spontaneously have to be cured by surgery which is complex and associated with a high morbidity. It is not considered traditional treatment to use the same medical therapy as in IBD to cure ECF caused by other conditions.A small case series has reported three patients with persistent ECF not related to IBD to have healed following use of Infliximab which is the treatment commonly used for ECF caused by IBD. Infliximab acts by inhibiting the activity of the inflammatory cytokine TNF- alpha. It is not known if this cytokine is present in ECF tissue in the absence of IBD.The aim of this study is to demonstrate the presence of inflammatory markers in tissue surrounding non-IBD ECF and in particular to quantify the presence of the cytokine TNF- alpha. We hypothesise that TNF - alpha levels are raised in non-IBD ECF. METHODS/DESIGN: Tissue and serum from ECF of IBD and non-IBD patients will be prospectively collected at St. Mark's Hospital Intestinal Failure Unit. The control group will consist of patients undergoing colonoscopy for bowel cancer screening, with normal findings. Biopsies of the terminal ileum will be obtained from this group during colonoscopy. The fistula tract and serum cytokine profiles of interleukins (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, TNF- alpha, IFN-y, MCP-1, EGF and VEGF will be assessed. DISCUSSION: This study aims to assess the presence or absence of TNF- alpha expression in the ECF tissue in non-IBD origin. If our hypothesis is correct we would then be able to study the use of the TNF- alpha inhibitor Infliximab as a therapeutic option in the treatment of non-IBD ECF. Secondary aims include assessing the spectrum of inflammatory cytokines and markers present in tissue and serum of non-IBD ECF when compared with IBD ECF and normal controls. TRIAL REGISTRATION: ISRCTN44000447.

Refeeding hypophosphataemia is more common in enteral than parenteral feeding in adult in patients.

BACKGROUND & AIMS: Refeeding hypophosphataemia (RH) can result in sudden death. This study aimed to compare the incidence of RH between patients fed enterally and those fed parenterally. METHODS: The risk of RH in adult patients fed parenterally (PN) or nasogastrically (NG) was assessed by comparison of patient records with the UK NICE guidelines for refeeding syndrome, between December 2007 and December 2008. A fall in serum phosphate to less than 0.6 mmol/L was indicative of RH. RESULTS: Of 321 patients,92 were at risk of RH. Of these, 23 (25%) patients developed RH (p = 0.003). 18 (33%) of NG fed, 'at-risk' patients developed RH vs 5 (13%) fed parenterally (p = 0.03). Death within 7 days and RH were not associated. The sensitivity and specificity of the NICE criteria for defining patient's risk of RH was calculated: 0.76 and 0.50 respectively for NG feeding; 0.73 and 0.38 respectively for parenteral feeding. CONCLUSION: Patients fed by NG tube and deemed at risk of RH are more likely to develop RH than patients fed by PN. The higher risk with NG feeding may be due to the incretin effect from absorption of glucose. The UK guidelines lack specificity.

Survey on the use of adalimumab as maintenance therapy in Crohn's disease in England and Ireland.

INTRODUCTION: Adalimumab is effective in inducing and maintaining response/remission in patients with Crohn's disease either naive to biological therapies or after secondary failure of infliximab. AIM: To present the first 'real-life' survey data from England and Ireland on the use of adalimumab. METHOD: A retrospective audit conducted through a web-based questionnaire in England/Ireland. RESULTS: We analysed data on 61 patients (35 female, 26 male) with a median age of 33 years (range 17-71 years) and an average follow-up of 8 months. The maximal maintenance dose was 40 mg every other week in 84% of patients, 40 mg weekly in 13% and 80 mg weekly in 3%. Maintenance adalimumab achieved remission in 57% of patients. The ongoing response rate was 83.6%. An additional 8% had a secondary loss of response after an average of 8.4 months (range 2-17). Adverse effects were observed in 23% of patients: of which there was local pain in 29%, infection in 36%, headaches in 14%, leucopenia (on azathioprine) in 7%, a painful rash in 7% and serum-sickness-type reaction in 7%. Adverse events led to discontinuation in two patients. CONCLUSION: This English/Irish audit shows an acceptable response/remission and safety profile of adalimumab in the treatment of Crohn's disease. In contrast to earlier data from Scotland, dose escalation was only observed in 16% of patients. The majority of responders were steroid-free at follow-up.

Detection of muramyl dipeptide-sensing pathway defects in patients with Crohn's disease.

BACKGROUND AND AIMS: Crohn's disease is strongly associated with double mutations in NOD2/CARD15. Three common mutations (Arg702Trp, Gly908Arg, Leu1007fs) impair innate immune responses to bacterial muramyl dipeptide. Rare NOD2 variants occur, but it is difficult to both identify them and assess their functional effect. We assessed the true frequency of defective muramyl dipeptide sensing in Crohn's disease and developed a rapid diagnostic assay. MATERIALS AND METHODS: An ex vivo assay was established and validated based on muramyl dipeptide stimulation of peripheral blood mononuclear cell cytokine production. Muramyl dipeptide-induced enhancement of interleukin (IL)-8 secretion and synergistic increase in lipopolysaccharide-induced IL-1beta secretion were studied. Assay results were compared with NOD2 genotype status (3 common mutations and rare variants) in 91 individuals including a prospective cohort of 49 patients with Crohn's disease. RESULTS: The assay was highly sensitive and specific for detection of profound defects in muramyl dipeptide sensing caused by double NOD2 mutations (IL-8 P = 0.0002; IL-1beta P = 0.0002). Disease state, active inflammation, or concurrent use of immunosuppressive medication did not influence results. Healthy NOD2 heterozygotes had modest impairment of muramyl dipeptide induced IL-8 secretion (P = 0.003). Only 1 of 7 patients with Crohn's disease with both a common mutation and a rare variant had a profound muramyl dipeptide-sensing defect. CONCLUSIONS: Profound defects in muramyl dipeptide sensing were found in 10% of patients with Crohn's disease. Defects were caused exclusively by inherited mutations in NOD2. The ex vivo assay has multiple potential applications as a clinical diagnostic tool to distinguish patients with muramyl dipeptide-sensing defects and for research investigation.