Adult Intestinal and Multivisceral Transplantation: Experience From a Single Center in the United Kingdom.

Cambridge is one of two designated adult intestinal transplant centers in the United Kingdom and has performed 60 transplants on 54 patients since 2007; 52% of these were undertaken in the last 3 years. This increasing trend is in contrast with that reported worldwide; 27% were small bowel grafts (SBT), 15% modified multivisceral (MMVT), and 58% multivisceral (MVT). Median recipient age was 47 years; the female-to-male ratio was 27/33. Primary diseases included visceral arterial thromboses (17%), Crohn's disease (17%), motility disorders (12%), visceral venous thromboses (12%), familial adenomatous polyposis (FAP)/desmoids (8%), alcoholic cirrhosis (3%), nonalcoholic fatty liver disease (3%), ulcerative colitis (2%), and other (15%). Indications for transplant included intestinal failure-associated liver disease (IFALD) (27%), loss of central venous access (17%), FAP/desmoid disease (5%), extensive portomesenteric venous thrombosis (PMVT) (20%), widespread mesenteric arterial ischemia (WMAI) (13%), re-transplant (8%), and other (10%). Overall 1-year/5-year patient survival rates were 77%/62%. One-year/5-year patient survival rates were 92%/83%, 85%/65%, and 71%/33% for SBT, MMVT, and MVT. One-year/5-year survival rates for patients with IFALD, PMVT, and other indications who underwent MVT were 80%/20%, 65%/55%, and 55%/35%. The greatest proportion of patient deaths occurred during the first year after transplant (50% in year 1, 23% in year 2, 9% in year 3, 5% in year 4, and 14% in year 5), particularly in the MVT group. Referrals to our United Kingdom center are increasing, and the indications for transplant are becoming more diverse. Our patient survival rates remain comparable with figures reported worldwide.

Quality of life and performance status before and after small intestinal transplantation.

INTRODUCTION: Intestinal transplantation (IT) is considered for patients with irreversible intestinal failure who develop life-threatening complications of parenteral nutrition or have extensive intra-abdominal disease requiring evisceration. Developing indications may include quality of life (QOL) considerations and therefore assessment of QOL and performance status (PS) after IT is important. We report QOL and PS before and after IT in our cohort. METHODS: Consecutive patients undergoing IT were included. QOL was assessed using the generic 36-item short form survey (SF 36) tool at assessment and 6-month intervals post-transplantation. Performance was assessed using a visual analogue scale (VAS), Karnofsky scale (KS), and the Eastern Cooperative Oncology Group scale at three time points: premorbidly, at listing, and after transplantation. RESULTS: Data were available for 21 patients. There were 11 complete SF 36 datasets and 15 performance scores. Data were not available from 3 patients, and the overall response rate was 62%. Overall, there was a trend for improved SF 36 scores post-transplantation in approximately half of the patients with scores remaining stable in approximately one third. The results of the SF 36 significantly improved in 1 patient (P < .01). After IT, 66% of patients had better VAS scores than at listing and >75% of patients scored better or the same in KS compared to status at listing. However, PS after IT did not improve to premorbid levels. CONCLUSION: We found a trend for QOL scores to improve in approximately half of the patients compared to their status at listing, remain static in approximately one third, and a minority experience a decline. For the majority, differences were not statistically significant. PS of patients after transplantation is equal or better than that at listing in 75%, but rarely reaches that of the premorbid status. Longer-term studies are needed and may reveal progressive improvement.

Adult small intestinal and multivisceral transplantation: lessons through the "retrospecto-scope" at a single UK centre from 1991 to 2013.

The first intestinal transplantation in the United Kingdom was performed in Cambridge in 1991. Thirty-eight intestinal transplantations have since been performed in 35 patients. All deaths in the first postoperative month related to hemorrhage, in 2 cases to severe portal hypertension (SPH) and poor venous access in 2. We have modified our practice to reduce the bleeding risk with SPH. Loss of venous access can be avoided by timely referral. Rejection was implicated in 3/14 deaths all dying of sepsis. Cytomegalovirus disease resulted in 2 deaths; we try to avoid CMV-positive donors giving to CMV-negative recipients. Three deaths were related to psychiatric illness, which led to loss of graft in 2 others. Three patients were retransplanted (2 rejections and 1 infarction) and all remain alive. Most patients (10/13) experienced a fall in body weight in the first postoperative year after SB/MV transplantation. Body weight fell by as much as 25%. As transplantation resulted in a net gain in small bowel in most cases, the postoperative loss of native body weight may be underestimated. Interestingly this was not associated with a significant fall in midarm circumference or handgrip strength. Long-term nutrition can be maintained with oral intake in the majority of patients post-SBT. There is improvement in handgrip strength post-transplant. Transplantation does not significantly alter weight, albumin, or other common anthropometric markers. Despite these problems, our 5-year survival results remain relatively good at 73% in the cohort from 1991, 79% from 2003, and 80% from 2008. We consider that deployment of strategies learned from our experiences has improved outcomes.

Psychiatric disorders in patients undergoing intestinal transplantation.

BACKGROUND: Psychiatric disorders are common in chronic disease states; intestinal transplantation recipients may therefore be at high risk for psychiatric disorder (PD). We sought to investigate the frequency and type of PD in our cohort of patients undergoing transplantation between 2007 and 2012. RESULTS: The notes of 25 patients who had undergone transplantations since 2007 were available for analysis. Five of 25 patients had died at the time of data collection. Pretransplantation, 14 of 25 patients had a history of a single psychiatric disorder (SPD) (depression). Two of 25 had double psychiatric diagnoses (DPD; depression with anxiety), and 1 had three PDs. Three of 25 patients suffered from chronic pain syndrome and 1 patient had this as an isolated diagnosis without any other PD. Post-transplantation, 10 of 14 patients still had an SPD; however, 3 of 14 had acquired a second diagnosis (DPD; anxiety with depression) with suicidal ideation in 2 cases. Those with DPD preoperatively did not improve. Depression resolved in 1 of 14 after transplantation. One patient without a history of psychiatric issues developed DPD during the postoperative course. Only 3 of 25 surviving patients are free of any psychological diagnosis post-transplantation. The presence of other problems in the cohort such as chronic pain syndrome in 4 of 25, medical noncompliance in 3 of 25, cyclizine dependency in 2 of 25, and recreational drug use suspected in 1 were also identified. Problems with body image relating to the stoma were experienced by 2 of 25 patients. CONCLUSION: The incidence of psychiatric disorder in patients embarking on transplantation is high and relates to their history of chronic illness. The additional stress of the transplantation operation and the long in-hospital rehabilitation period takes its toll on patients' emotional health and many acquire further psychiatric diagnoses. Managing the psychiatric health of patients is important for successful rehabilitation and their long-term health and wellbeing.

Occult invasive aspergillosis infection following multivisceral transplantation.

Patients undergoing multivisceral transplantation are particularly susceptible to post-operative infections due to immunosuppression and the inclusion of bowel in the transplanted graft. These patients typically receive broad-spectrum antimicrobial and antifungal agents as prophylaxis and treatment. However, evidence for this is limited due to the small number of patients undergoing the procedure. We present a case of occult disseminated invasive aspergillosis infection in a patient who underwent multivisceral transplantation.

Cambridge-Miami score for intestinal transplantation preoperative risk assessment: initial development and validation.

INTRODUCTION: Preoperative quantification of survival after transplantation would assist in assessing patients. We have developed a preliminary preoperative scoring system, called the Cambridge-Miami (CaMi) score, for transplantation of the small intestine either alone or as a composite graft. METHODS: The score combines putative risk factors for early-, medium-, and long-term survival. Factors included were loss of venous access and impairment of organs or systems not corrected by transplantation. Each factor was scored 0-3. A score of 3 indicated comorbidity approaching a contraindication for transplantation, that which might lead to but was not currently an adverse risk factor scored 1, and that presenting a definite but moderate increase in risk scored 2. The preoperative scores of 20 patients who had received intestinal transplants either isolated or as part of a cluster graft, who had either been followed up postoperatively for at least 10 years, or died within 10 years were compared with their survivals. RESULTS: Postoperative survival and CaMi score inversely correlated when analysed using Spearman test (r(s) = -0.82; P = .0001). A score of <3 associated with survival > or =3 years (12/12 patients) and >3 with survival of <6 months (4/4). Patient Kaplan-Meier (KM) survival curves for patients grouped according to CaMi score became significantly different from group 0 to group 3. Using this as a threshold score patients grouped as either >2 or <3 had significantly different survival rates (log-rank; P = .0001), KM median survival hazard ratio (HR) = 6, and rate of death KM HR = 5. Receiver-operator characteristics indicate a high degree of accuracy for prediction of death with an area under the curve (C statistic) at 3 years of 0.98, at 5 years of 0.82, and at 10 years of 0.65. CONCLUSION: This initial validation suggested that the preoperative CaMi score predicted postoperative survival.

Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome.

AIM: To investigate the efficacy and safety of renzapride, a potent 5-hydroxytryptamine type-4 receptor full agonist and 5-hydroxytryptamine type-3 receptor antagonist in patients with constipation-predominant irritable bowel syndrome. METHODS: In this dose-escalating pilot study, 17 patients with constipation-predominant irritable bowel syndrome received placebo, renzapride 2 mg o.d. and renzapride 2 mg b.d. sequentially for 28 days. Response was determined by radio-opaque marker measurement of overall gastrointestinal and segmental colonic transit and patients' assessment of their irritable bowel syndrome symptoms. RESULTS: Renzapride reduced mean overall gastrointestinal transit time (placebo, 2.9 +/- 1.6 days; renzapride 2 mg o.d., 2.6 +/- 1.4 days; renzapride 2 mg b.d., 1.9 +/- 1.6 days) (P = 0.024) and accelerated segmental colonic transit, with statistically significant differences for renzapride 2 mg b.d. over placebo in caecum/ascending colon (P = 0.019) and descending colon (P = 0.022). Renzapride also reduced abdominal pain, increased the number of pain-free days and improved stool consistency. The frequency of reported adverse events was similar on renzapride and placebo. CONCLUSIONS: Renzapride is well-tolerated, stimulates gastrointestinal transit and improves symptoms in patients with constipation-predominant irritable bowel syndrome, particularly at the 2 mg b.d. dose, where improvements in gastrointestinal symptoms were evident over placebo. This study has established proof of concept and supports further investigation of renzapride in patients with constipation-predominant irritable bowel syndrome.

Diagnosis of oesophageal cancer by detection of minichromosome maintenance 5 protein in gastric aspirates.

Symptomatic oesophageal cancer is usually advanced and the prognosis poor. Lethality of symptomatic oesophageal cancer has motivated screening for these diseases earlier in their evolution, but reliable methods for early diagnosis remain elusive. We have demonstrated that dysregulated expression of minichromosome maintenance (MCM) proteins 2-7 is characteristic of early epithelial carcinogenesis, and that these key DNA replication initiation factors can be used as diagnostic markers for cervical and genito-urinary tract cancer. In this study, we investigated whether minichromosome maintenance protein 5 (Mcm5) can be used to detect oesophageal cancer cells in gastric aspirates. Two monoclonal antibodies raised against His-tagged human Mcm5 were used in a time-resolved immunofluorometric assay to measure Mcm5 levels in cells isolated from gastric aspirates of 40 patients undergoing gastroscopy for suspected or known oesophageal carcinoma or symptoms of dyspepsia. The test discriminated with high specificity and sensitivity between patients with and without oesophageal cancer (85% sensitivity (95% confidence interval (CI)=62-97%), 85% specificity (CI=66-96%)), as demonstrated by the large area under the receiver operating characteristics curve (0.93 (95% CI=0.85-0.99)). Elevated levels of Mcm5 in gastric aspirates are highly predictive of oesophageal cancer. This simple test for oesophageal cancer is readily automated with potential applications in primary diagnosis, surveillance and screening.

Adult small intestinal transplantation in England and Wales.

BACKGROUND: In 1996 two transplantation centres in the UK were commissioned by the National Specialist Commissioning Advisory Group for England and Wales to assess small intestinal transplantation in adults. The joint experience of the two centres is presented. METHODS: Patients with irreversible small intestinal failure and complications of parenteral nutrition, and those with abdominal disease requiring extensive visceral resection, were assessed as candidates and where appropriate listed for surgery. RESULTS: Thirty-six patients were assessed for small intestinal transplantation and, of these, 14 underwent surgery. Twelve patients survived the transplantation procedure. Of these, seven patients were alive at 1 year, five at 3 years and three at 5 years. Three patients remain alive. Patient and graft survival improved with experience; the 1-year survival rate improved in the last 4 years of this experience from 43 to 57 per cent, and the 3-year survival rate from 29 to 43 per cent. CONCLUSION: Small intestinal transplantation is associated with a high mortality rate but may benefit carefully selected patients in whom conservative management is likely to carry a greater mortality rate.

Relapsing encephalopathy following small bowel transplantation.

We report a case of a 40-year-old man presenting with relapsing encephalopathy 4 years post-intestinal transplantation. Each episode was preceded by symptoms suggestive of subacute intestinal obstruction, marked dehydration, and, on one occasion, grade 4 encephalopathy. Physical examination revealed hypertonia, clonus, and hyperreflexia. Biochemistry was consistent with renal impairment, metabolic alkalosis, hyperammonaemia, and normal liver function. Plain radiographs and abdominal computed tomography revealed dilated proximal small bowel loops, and barium radiography demonstrated a strictured distal anastomosis. Hydrogen breath testing indicated bacterial overgrowth. Following rehydration and antibiotic therapy, the patient recovered fully between episodes. Further episodes of encephalopathy did not recur following resection of the distal anastomotic stricture and resolution of bacterial overgrowth. Unfortunately, one year later the patient died of pneumonia. To the best of our knowledge, encephalopathy secondary to intestinal transplant related porto-caval shunt and bacterial overgrowth in strictured bowel has not been previously reported but might have implications for the management of future patients.

Oral prednisolone metasulphobenzoate in the treatment of active ulcerative colitis.

BACKGROUND: Corticosteroids are one of the mainstays of treatment for active ulcerative colitis, but they are associated with numerous side effects. The sparingly absorbed corticosteroid prednisolone metasulphobenzoate is used topically in the treatment of distal disease. A targeted-release oral preparation (Predocol) has been developed to allow delivery of this drug to the whole colon. We have studied the effect of oral Predocol on inflammation as measured by 99Tc(m)-HMPAO leucocyte scintigraphy in patients with symptomatic and sigmoidoscopic relapse of known extensive ulcerative colitis. METHODS: Fourteen patients were recruited and received Predocol 47.1 mg twice daily, 8 for 7 days and 6 for 14 days. Scintigraphy was performed prior to and at the end of treatment. Each segment of colon was graded (0-4) and individual scores summed to give a total scintigraphic score. RESULTS: Total scintigraphic score improved by a mean of 2.5 (P = 0.027). Mean individual scores improved in the rectum by 0.7 (P = 0.038) and in the descending colon by 0.8 (P = 0.033). CONCLUSIONS: Predocol is an oral preparation of a poorly absorbed salt of prednisolone that is effective in reducing inflammation over short treatment periods in patients with active ulcerative colitis.

A family history study of chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is characterized by unexplained, disabling fatigue and is associated with high rates of comorbid depression. While the aetiology is unknown, findings from recent twin surveys suggest that genetic factors may be relevant to prolonged fatigue states (> 1 month). To date, however, there has been no exploration of the role of familial/genetic factors in operationally defined CFS. The aims of the present study were: (i) to examine whether CFS is familial by comparing the rates of CFS in the first-degree relatives of CFS cases and medical control subjects; and (ii) to determine whether the high rate of comorbid depression in CFS is reflected in a greater familial loading for affective disorder. Twenty-five CFS cases and 36 medical control subjects were assessed for fatigue symptoms based on the Centre for Disease Control (CDC) criteria for CFS, and for lifetime psychiatric symptoms using the Schedule for Schizophrenia and Affective Disorders-Lifetime Version. Informant family history was obtained regarding first-degree relatives using the CDC criteria and the Family History Research Diagnostic Criteria. In addition, informant history was supplemented by sending a questionnaire to first-degree relatives. There were significantly higher rates of CFS in the relatives of CFS cases compared with the relatives of control subjects. The rate of depression in the CFS cases was similar to previous studies but did not appear to reflect a greater familial loading for depression when compared with control subjects. However, these analyses were complicated by higher than expected rates of depression in the control group. These findings suggest that familial factors are important in the aetiology of chronic fatigue syndrome.

The physiological expression of inducible nitric oxide synthase (iNOS) in the human colon.

BACKGROUND: Inducible nitric oxide synthase (iNOS) is expressed in the colonic epithelium in both inflammatory bowel disease and colorectal cancer. Nitric oxide (NO), the product of this enzyme, has been implicated in the pathogenesis of both conditions. However, there are conflicting data on whether iNOS is expressed in the normal, uninflamed human colon. AIMS: To evaluate the expression of iNOS in histologically normal, non-inflamed human colonic mucosa. PATIENTS/METHODS: Reverse transcription polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemistry were used to investigate the expression of iNOS in 17 histologically normal specimens obtained at colectomy performed for colorectal neoplasia. In addition, 16 endoscopic mucosal biopsies, taken from normal individuals, were also evaluated. Eleven surgical specimens and 16 endoscopic biopsies from patients with refractory ulcerative colitis were used as inflammatory controls. RESULTS: All types of specimens expressed iNOS mRNA. Immunoblotting revealed a protein of approximately 130 kDa consistent with iNOS in mucosal extracts of 77% of normal individuals, and 85% of diseased controls. Immunolabelling localised this protein to the surface epithelium in most of the normal specimens and also to the crypt epithelium and inflammatory cells in the diseased controls. CONCLUSIONS: These findings provide evidence that iNOS is often expressed in the surface epithelium of non-inflamed human colon, suggesting that it is induced by local luminal factors, such as bacterial lipopolysaccharide (endotoxin). The resultant NO produced at this site might act as an oxidative barrier, reducing bacterial translocation and providing a means of defence against pathogenic microorganisms.

Neuronal COX-2 expression in human myenteric plexus in active inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with changes in colonic motility which may contribute to the pain and diarrhoea associated with exacerbations of this disease. These changes may be mediated by prostaglandins which are increased in this condition. Increased expression of the inducible isoform of cyclo-oxygenase (COX-2) has been found in active IBD although its cellular distribution remains uncertain. AIMS: To evaluate the cellular distribution of COX-2 in active IBD. PATIENTS AND METHODS: Using reverse transcription-polymerase chain reaction, in situ hybridisation, and immunohistochemistry, COX-2 expression was evaluated in 12 colectomy specimens from patients with active ulcerative colitis (UC), and six specimens from patients with Crohn's colitis that had failed medical therapy. Histologically normal colon was obtained from 12 patients having resection for colorectal neoplasia and evaluated as above, acting as control specimens. RESULTS: All specimens expressed COX-2 mRNA, with some 6-8-fold increase in inflamed tissues on densitometric analysis (both UC and Crohn's) compared with controls. In situ hybridisation localised this mRNA to myenteric neural cells, surrounding smooth muscle cells, and inflammatory cells of the lamina propria in the IBD specimens, with some weaker labelling seen in the epithelium. No COX-2 labelling was seen in normal tissues. Immunohistochemistry confirmed these sites of COX-2 expression in all inflamed specimens, with absence of immunoreactivity in control tissues. CONCLUSIONS: These findings provide the first evidence of COX-2 expression in neural cells of the myenteric plexus in active IBD which, via increased prostaglandin synthesis at this site, may contribute to the dysmotilty seen in this condition.

Evaluation of the effectiveness of a specialist nurse in the management of inflammatory bowel disease (IBD).

OBJECTIVE: To determine the effect of a specialist nurse on the management outcome of patients with inflammatory bowel disease (IBD). DESIGN: Audit of the management of a cohort of patients in the year prior to the employment of the specialist nurse and the year immediately after. SUBJECTS: 339 patients, both male and female, with either Crohn's disease or ulcerative colitis, resident in the Cambridge health district. SETTING: Addenbrooke's Hospital NHS Trust Outpatient Centre. MAIN OUTCOME MEASURE: Health status was measured by blood tests (C-reactive protein, albumin and haemoglobin) throughout the year, symptom indices, number of clinic attendances, admissions to hospital and length of stay. Quality of life was measured via a postal questionnaire. RESULTS: Hospital visits were reduced from 1377 to 853 (38% reduction) and in-patient length of stay measured in bed-days from 516 to 417 (19% reduction). The number of patients in remission increased from 63 to 69%. Patient satisfaction improved in key areas, in particular, access to information on IBD and advice on avoidance of illness and maintaining health. Of a total of 251 calls to the telephone helpline, only 19 patients were referred for a medical opinion and five patients required hospital admission. CONCLUSION: The IBD nurse specialist is a valuable and cost-effective member of the gastroenterology team.