Inflammatory pouch disease: The spectrum of pouchitis

Restorative proctocolectomy with ileal-pouch anal anastomosis(IPAA) is the operation of choice for medically refractory ulcerative colitis(UC), for UC with dysplasia, and for familial adenomatous polyposis(FAP). IPAA can be a treatment option for selected patients with Crohn's colitis without perianal and/or small bowel disease. The term "pouchitis" refers to nonspecific inflammation of the pouch and is a common complication in patients with IPAA; it occurs more often in UC patients than in FAP patients. This suggests that the pathogenetic background of UC may contribute significantly to the development of pouchitis. The symptoms of pouchitis are many, and can include increased bowel frequency, urgency, tenesmus, incontinence, nocturnal seepage, rectal bleeding, abdominal cramps, and pelvic discomfort. The diagnosis of pouchitis is based on the presence of symptoms together with endoscopic and histological evidence of inflammation of the pouch. However, "pouchitis" is a general term representing a wide spectrum of diseases and conditions, which can emerge in the pouch. Based on the etiology we can sub-divide pouchitis into 2 groups: idiopathic and secondary. In idiopathic pouchitis the etiology and pathogenesis are still unclear, while in secondary pouchitis there is an association with a specific causative or pathogenetic factor. Secondary pouchitis can occur in up to 30% of cases and can be classified as infectious, ischemic, non-steroidal antiinflammatory drugs-induced, collagenous, autoimmuneassociated, or Crohn's disease. Sometimes, cuffitis or irritable pouch syndrome can be misdiagnosed as pouchitis. Furthermore, idiopathic pouchitis itself can be sub-classified into types based on the clinical pattern, presentation, and responsiveness to antibiotic treatment. Treatment differs among the various forms of pouchitis. Therefore, it is important to establish the correct diagnosis in order to select the appropriatetreatment and further management. In this editorial, we present the spectrum of pouchitis and the specific features related to the diagnosis and treatment of the various forms.     

Fecal microbiota in pouchitis and ulcerative colitis

AIM To investigate the changes in microbiota in feces of patients with ulcerative colitis(UC) and pouchitis using genomic technology.METHODS Fecal samples were obtained from UC patients with or without an ileal pouch-anal anastomosis(IPAA) procedure, as well as healthy controls. The touchdown polymerase chain reaction technique was used to amplify the whole V3 region of the 16 S r RNA gene, which was transcribed from DNA extracted from fecal samples. Denaturing gradient gel electrophoresis was used to separate the amplicons. The band profiles and similarity indices were analyzed digitally. The predominant microbiota in different groups was confirmed by sequencing the 16 S rR NA gene. RESULTS Microbial biodiversity in the healthy controls was significantly higher compared with the UC groups(P 0.001) and IPAA groups(P 0.001). Compared with healthy controls, the UC patients in remission and those in the mildly active stage, the predominant species in patients with moderately and severely active UC changed obviously. In addition, the proportion of the dominant microbiota, which was negatively correlated with the disease activity of UC(r =-6.591, P 0.01),was decreased in pouchitis patients. The numbers of two types of bacteria, Faecalibacterium prausnitzii and Eubacterium rectale, were reduced in UC. Patients with pouchitis had an altered microbiota composition compared with UC patients. The microbiota from pouchitis patients was less diverse than that from severely active UC patients. Sequencing results showed that similar microbiota, such as Clostridium perfringens, were shared in both UC and pouchitis.CONCLUSION Less diverse fecal microbiota was present in patients with UC and pouchitis. Increased C. perfringens in feces suggest its role in the exacerbation of UC and pouchitis.     

Evaluation of inflammatory activity in Crohn's disease and ulcerative colitis

Crohn's disease and ulcerative colitis evolve with a relapsing and remitting course. Determination of inflammatory state is crucial for the assessment of disease activity and for tailoring therapy. However, no simple diagnostic test for monitoring intestinal inflammation is available. Noninvasive markers give only indirect assessments of disease activity. Histopathological or endoscopical examinations accurately assess inflammatory activity, but they are invasive, time consuming and expensive and therefore are unsuitable for routine use. Imaging procedures are not applicable for ulcerative colitis. The usefulness of ultrasound and Doppler imaging in assessing disease activity is still a matter of discussion for Crohn's disease, and an increased interest in computed tomography enterograph (CTE) has been seen, mainly because it can delineate the extent and severity of bowel wall inflammation, besides detecting extraluminal findings. Until now, the available data concerning the accuracy of magnetic resonance enterography in detecting disease activity is less than CTE. Due to this, clinical activity indices are still commonly used for both diseases.     

Anatomic extent of colitis and disease severity are not predictors of pouchitis after restorative proctocolectomy for mucosal ulcerative colitis

Background Pouchitis is a common complication following restorative proctocolectomy with ileal pouch anal anastomosis (RPC–IPAA) for mucosal ulcerative colitis (MUC). The aim of this study was to determine if perioperative anatomic extent and severity of disease are predictors of pouchitis. Methods All consecutive patients who underwent RPC–IPAA for MUC between 1988 and 2002 were retrospectively studied. Pouchitis was classified as acute, recurrent or refractory. Colectomy specimen slides were histopathologically evaluated by a single blinded pathologist (MB), who assessed extent and severity of disease. Results Of 112 patients assessed, 70 (62.5%) had some form of pouchitis at a median follow–up of 38 months (range, 1–204 months). No association was found between the extent or severity of disease and subsequent development of acute or chronic pouchitis. A positive correlation was found between the histopathologic score and the occurrence of clinical pouchitis (p=0.014). The presence of colonic metaplasia in the pouch biopsy was significantly correlated with a histopathologic diagnosis of pouchitis (p<0.0001, r=–0.449). Conclusions Following RPC for MUC, the extent and severity of disease do not predict the subsequent development of pouchitis.     

Possible role of human cytomegalovirus in pouchitis after proctocolectomy with ileal pouch-anal anastomosis in patients with ulcerative colitis

AIMTo detect the presence of human cytomegalovirus(HCMV)proteins and genes on the ileal pouch of patients with ulcerative colitis who have undergone proctocolectomy with ileal pouch-anal anastomosis(IPAA).METHODSImmunohistochemistry,polymerase chain reaction(PCR)and PCR sequencing methods were utilized to test the presence of HCMV in pouch specimens taken from 34 patients in 86 endoscopies.RESULTSHCMV genes and proteins were detected in samples from 12(35.2%)patients.The rate of detection was significant in the endoscopies from patients diagnosed with pouchitis(5 of 12,41.6%),according to the Japanese classification of pouchitis,in comparison to patients with normal pouch(7 of 62,11.2%;P = 0.021).In all patients with pouchitis in which the HCMV was detected,it was the first episode of pouchitis.The virus was not detected in previous biopsies taken in normal endoscopies of these patients.During the followup,HCMV was detected in one patient with recurrent pouchitis and in 3 patients whose pouchitis episodes improved but whose positive endoscopic findings persisted.CONCLUSIONHCMV can take part in the inflammatory process of the pouch in some patients with ulcerative colitis who have undergone proctocolectomy with IPAA.     

Laboratory markers in ulcerative colitis: Current insights and future advances

Ulcerative colitis(UC)and Crohn’s disease(CD)are the major forms of inflammatory bowel diseases(IBD)in man.Despite some common features,these forms can be distinguished by different genetic predisposition,risk factors and clinical,endoscopic and histological characteristics.The aetiology of both CD and UC remains unknown,but several evidences suggest that CD and perhaps UC are due to an excessive immuneresponse directed against normal constituents of the intestinal bacterial flora.Tests sometimes invasive are routine for the diagnosis and care of patients with IBD.Diagnosis of UC is based on clinical symptoms combined with radiological and endoscopic investigations.The employment of non-invasive biomarkers is needed.These biomarkers have the potential to avoid invasive diagnostic tests that may result in discomfort and potential complications.The ability to determine the type,severity,prognosis and response to therapy of UC,using biomarkers has long been a goal of clinical researchers.We describe the biomarkers assessed in UC,with special reference to acute-phase proteins and serologic markers and thereafter,we describe the new biological markers and the biological markers could be developed in the future:(1)serum markers of acute phase response:The laboratory tests most used to measure the acute-phase proteins in clinical practice are the serum concentration of C-reactive protein and the erythrocyte sedimentation rate.Other biomarkers of inflammation in UC include platelet count,leukocyte count,and serum albumin and serum orosomucoid concentrations;(2)serologic markers/antibodies:In the last decades serological and immunologic biomarkers have been studied extensively in immunology and have been used in clinical practice to detect specific pathologies.In UC,the presence of these antibodies can aid as surrogate markers for the aberrant host immune response;and(3)future biomarkers:The development of biomarkers in UC will be very important in the future.The progress of molecular biology tools(microarrays,proteomics and nanotechnology)have revolutionised the field of the biomarker discovery.The advances in bioinformatics coupled with cross-disciplinary collaborations have greatly enhanced our ability to retrieve,characterize and analyse large amounts of data generated by the technological advances.The techniques available for biomarkers development are genomics(single nucleotide polymorphism genotyping,pharmacogenetics and gene expression analyses)and proteomics.In the future,the additionof new serological markers will add significant benefit.Correlating serologic markers with genotypes and clinical phenotypes should enhance our understanding of pathophysiology of UC.     

Matrix metalloproteinases in the restorative proctocolectomy pouch of pediatric ulcerative colitis

AIM: To investigate matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pouch mucosa of pediatric onset ulcerative colitis (UC).METHODS: In this cross-sectional study, 28 patients with pediatric onset UC underwent ileal pouch biopsy 13 years (median) after proctocolectomy. Expression of MMPs-3, -7, -8, -9, -12 and -26 and TIMPs-1, -2 and -3 in samples was examined using immunohistochemichal methods, and another biopsy was used to evaluate the grade of histological inflammation. Two investigators independently graded the immunohistochemical specimens in a semiquantitative fashion, using a scale marking staining intensity as follows: 0 = less than 20 positive cells; 1 = 20-50 positive cells; 2 = 50-200 positive cells; 3 = over 20 positive cells. Fecal calprotectin and blood inflammatory markers [serum C-reactive protein (CRP) and erythrocyte sedimentation rate] were determined during a follow-up visit to examine correlations between these markers and the expression of MMPs and TIMPs.RESULTS: Of the 28 patients with pediatric onset UC, nine had not experienced pouchitis, whereas thirteen reported a single episode, and six had recurrent pouchitis (≥ 4 episodes). At the time of the study, six patients required metronidazole. In all of the others, the most recent episode of pouchitis had occurred over one month earlier, and none were on antibiotics. Only four samples depicted no sign of inflammation, and these were all from patients who had not had pouchitis. Two samples were too small to determine the grade of inflammation, but both had suffered pouchitis, the other recurrent. No sample depicted signs of colonic metaplasia. Most pouch samples showed expression of epithelial (e) and stromal (s) MMP-3 (e, n = 22; s, n = 20), MMP-7 (e, n = 28; s, n = 27), MMP-12 (e, n = 20; s, n =24), TIMP-2 (e, n = 23; s, n = 23) and MMP-3 (e, n = 23; s, n = 28) but MMP-8 (e, n = 0; s, n = 1), MMP-9 (e, n = 0; s, n = 9) and MMP-26 (e, n = 0; s, n = 3) and TIMP-1 (n = 0, both) were lacking. In samples with low grade of inflammatory activity, the epithelial MMP-3 and MMP-7 expression was increased (r = -0.614 and r = -0.472, respectively, P < 0.05 in both). MMPs and TIMPs did not correlate with the markers of inflammation, fecal calprotectin, erythrocyte sedimentation rate, or CRP, with the exception of patients with low fecal calprotectin (< 100 μg/g) in whom a higher expression of epithelial MMP-7 was found no differences in MMP- or TIMP-profiles were seen in patients with a history of pouchitis compared to ones with no such episodes. Anastomosis with either straight ileoanal anastomosis or ileoanal anastomosis with J-pouch did depict differences in MMP- or TIMP-expression.CONCLUSION: The expression of MMPs pediatric UC pouch in the long-term shares characteristics with inflammatory bowel disease, but inflammation cannot be classified as a reactivation of the disease.     

Ileal pouch surgery for ulcerative colitis

Ulcerative colitis （UC） is a relapsing and remitting disease characterised by chronic mucosal and submucosal inflammation of the colon and rectum. Treatment may vary depending upon the extent and severity of inflammation. Broadly speaking medical treatments aim to induce and then maintain remission. Surgery is indicated for inflammatory disease that is refractory to medical treatment or in cases of neoplastic transformation. Approximately 25% of patients with UC ultimately require colectomy. Ileal pouch-anal anastomosis （IPAA） has become the standard of care for patients with ulcerative colitis who ultimately require colectomy. This review will examine indications for IPAA, patient selection, technical aspects of surgery, management of complications and long term outcome following this procedure.     

Crohn’s and colitis in children and adolescents

Crohn’s disease and ulcerative colitis can be grouped as the inflammatory bowel diseases (IBD). These conditions have become increasingly common in recent years, including in children and young people. Although much is known about aspects of the pathogenesis of these diseases, the precise aetiology is not yet understood, and there remains no cure. Recent data has illustrated the importance of a number of genes-several of these are important in the onset of IBD in early life, including in infancy. Pain, diarrhoea and weight loss are typical symptoms of paediatric Crohn’s disease whereas bloody diarrhoea is more typical of colitis in children. However, atypical symptoms may occur in both conditions: these include isolated impairment of linear growth or presentation with extra-intestinal manifestations such as erythema nodosum. Growth and nutrition are commonly compromised at diagnosis in both Crohn’s disease and colitis. Consideration of possible IBD and completion of appropriate investigations are essential to ensure prompt diagnosis, thereby avoiding the consequences of diagnostic delay. Patterns of disease including location and progression of IBD in childhood differ substantially from adult-onset disease. Various treatment options are available for children and adolescents with IBD. Exclusive enteral nutrition plays a central role in the induction of remission of active Crohn’s disease. Medical and surgical therapies need to considered within the context of a growing and developing child. The overall management of these chronic conditions in children should include multi-disciplinary expertise, with focus upon maintaining control of gut inflammation, optimising nutrition, growth and quality of life, whilst preventing disease or treatment-related complications.     

Use of cyclosporin retention enemas in a patient with intractable pouchitis after proctocolectomy for ulcerative colitis: a case report

We report the case of a 46-year-old male with a 24-year history of ulcerative colitis who underwent proctocolectomy and ileal S-pouch-anal anastomosis. Six months after surgery the patient complained of increased daytime bowel frequency; pouchoscopy revealed severe pouchitis. Because of the failure of conventional treatments, the patient underwent a cycle of cyclosporin A (CsA) enemas. The therapy consisted of one enema each day for 5 weeks (35 administrations). The patient was submitted to a total of five pouchoscopies, the first before the beginning of the enemas cycle and the last one 2 months after the end of the treatment, Endoscopy showed a remarkable improvement at day 10, but these findings were not confirmed later. Biopsies showed a marked improvement at 10 days, but at later stages a reappearance of crypt abscesses with an increasing number of inflammatory infiltrates. In spite of the grim picture at endoscopy and histology, the patient felt better and noted a progressive reduction of the bowel movements and cessation of mucous and bloody discharge. At present, he reports six bowel movements per day and no bleeding. Received: 2 October 1996 / Accepted in revised form: 6 January 1999     

Trefoil factors in inflammatory bowel disease

Inflammatory bowel disease(IBD),which comprises ulcerative colitis and Crohn’s disease,is characterized by inflammation of the gastrointestinal tract.The trefoil factors 1,2,and 3(TFF1-3)are a family of peptides that play important roles in the protection and repair of epithelial surfaces,including the gastrointestinal tract.TFFs may be involved in IBD pathogenesis and are a potential treatment option.In the present review,we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression,possible function and pharmacological role in IBD.     

一期全结肠直肠切除、回肠储袋肛管吻合术治疗溃疡性结肠炎的安全性及生活质量评估

目的探讨一期全结直肠切除、回肠储袋肛管吻合术（IPAA）治疗溃疡性结肠炎（UC）的安全性和术后生活质量。 方法回顾性分析四川大学华西医院胃肠外科中心2014年1月至2015年12月行一期IPAA治疗的22例UC患者的术中和术后临床资料及生活质量评分,探讨该术式的技术要点、安全性及生活质量。 结果22例患者均成功实施IPAA,共18例患者发生20例次并发症,其中,中-重度并发症（Clavien-Dindo Ⅲ~Ⅳ）2例次：1例发生胸腔积液行胸腔穿刺术,1例因术后肺部感染入ICU治疗,未发生储袋肛管吻合口漏。术后3月及12月时随访患者平均排便次数为（6.75±1.24）次/天和（4.18±1.00）次/天,克利夫兰总体生活质量评价（CGQL）为（0.85±0.08）及（0.92±0.06）。 结论对择期UC患者,采用一期IPAA治疗安全可行,术后患者排便功能及生活质量满意。     

Pouchitis in pediatric ulcerative colitis: A multicenter study on behalf of Italian Society of Pediatric Gastroenterology,Hepatology and Nutrition

BackgroundData on the epidemiology and risk factors for pouchitis following restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) in pediatric patients with ulcerative colitis (UC) are scarce.AimsTo determine incidence, risk factors and clinical outcome of pouchitis following IPAA in children.MethodsThis multicenter, retrospective cohort study, included all pediatric UC patients who underwent colectomy and IPAA from January 2010 to December 2016.ResultsEighty-five patients were enrolled. During a median post-surgical period of 24.8 (range: 1.0–72.0) months following IPAA, 38 (44.7%) patients developed pouchitis, including 6 (15.8%) who developed chronic pouchitis. Kaplan–Meier survival estimates of the cumulative probability for pouchitis were 14.6% at 1 year and 27.3% and 51.5% at 2 and 5 years, respectively. Multiple Cox regression model showed that older age at colectomy (hazard ratio, HR: 0.89, p = 0.008) was a protective factor, whereas chronic active colitis as indication for surgery (HR: 4.45, p < 0.001), and a 3-stage IPAA (HR: 2.86, p = 0.028) increased the risk for pouchitis.ConclusionsLong-term risk for pouchitis is significantly high in pediatric-onset UC after IPAA. Younger age at colectomy, chronic active colitis as indication for surgery and 3-stage IPAA may increase the risk for pouchitis.     

Frequency and associated factors of hair loss among patients with inflammatory bowel disease

AIM: To identify the frequency of hair loss among patients with inflammatory bowel disease(IBD) and associated clinical and disease related factors.METHODS: We performed a cross sectional study in a tertiary referral adult IBD clinic.Self-reported history and characteristics of hair loss as well as clinical and demographic information were collected.Data were analyzed using univariate and multivariate analyses.RESULTS: Two hundred and ten consecutive IBD patients were recruited; one hundred and fifty patients met predefined inclusion and exclusion criteria.Thirtythree percent of patients reported a history of hair loss.Age,gender,IBD type and disease duration were not associated with hair loss.Hair loss was reported less frequently among patients with use of mesalamine(54% vs 73%,P = 0.03) and antitumor necrosis factor medications(anti-TNF)(14% vs 40%,P = 0.001).In multivariate analyses adjusting for gender,IBD type and duration of disease,these associations with mesalamine and anti-TNF remained significant [(adjusted values for mesalamine(OR = 0.43,95%CI: 0.19-0.86) and anti-TNFs(OR = 0.28,95%CI: 0.08-0.98)].CONCLUSION: Hair loss is common among patients with IBD.Mesalamine and anti-TNF medications were associated with lower odds of hair loss.Further studies are required to assess the mechanism of hair loss among patients with IBD.     

Vaccines and recommendations for their use in inflammatory bowel disease

The patient with inflammatory bowel disease will be predisposed to numerous infections due their immune status. It is therefore important to understand the immune and serologic status at diagnosis and to put the patient into an adapted vaccination program. This program would be applied differently according to two patient groups: the immunocompromised and the non-immunocom-promised. In general, the first group would avoid the use of live-virus vaccines, and in all cases, inflammatory bowel disease treatment would take precedence over vaccine risk. It is important to individualize vaccination schedules according to the type of patient, the treatment used and the disease pattern.In addition, patient with inflammatory bowel disease should be considered for the following vaccines: varicella vaccine, human papilloma virus, influenza, pneumococcal polysaccharide vaccine and hepatitis B vaccine.     

Minimally invasive approaches for the treatment of inflammatory bowel disease

Despite significant improvements in medical management of inflammatory bowel disease, many of these patients still require surgery at some point in the course of their disease. Their young age and poor general conditions, worsened by the aggressive medical treatments, make minimally invasive approaches particularly enticing to this patient population. However, the typical inflammatory changes that characterize these diseases have hindered wide diffusion of laparoscopy in this setting, currently mostly pursued in high-volume referral centers, despite accumulating evidences in the literature supporting the benefits of minimally invasive surgery. The largest body of evidence currently available for terminal ileal Crohn’s disease shows improved short term outcomes after laparoscopic surgery, with prolonged operative times. For Crohn’s colitis, high quality evidence supporting laparoscopic surgery is lacking. Encouraging preliminary results have been obtained with the adoption of laparoscopic restorative total proctocolectomy for the treatment of ulcerative colitis. A consensus about patients’ selection and the need for staging has not been reached yet. Despite the lack of conclusive evidence, a wave of enthusiasm is pushing towards less invasive strategies, to further minimize surgical trauma, with single incision laparoscopic surgery being the most realistic future development.     

Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease

Inflammatory bowel diseases(IBDs) are chronic disorders of modern society, requiring management strategies aimed at prolonging an active life and establishing the exact etiology and pathogenesis.These idiopathic diseases have environmental, genetic,immunologic, inflammatory, and oxidative stress components. On the one hand, recent advances have shown that abnormal immune reactions against the microorganisms of the intestinal flora are responsible for the inflammation in genetically susceptible individuals. On the other hand, in addition to T helper cell-type(Th) 1 and Th2 immune responses,other subsets of T cells, namely regulatory T cells and Th17 maintained by IL-23 are likely to develop IBD. IL-23 acts on innate immune system members and also facilitates the expansion and maintenance of Th17 cells. The IL-17/IL-23 axis is relevant in IBD pathogenesis both in human and experimental studies. Novel biomarkers of IBD could be calprotectin,microRNAs, and serum proinflammatory cytokines.An efficient strategy for IBD therapy is represented by the combination of IL-17 A and IL-17 F in acute IL-17 A knockout TNBS-induced colitis, and also definite decrease of the inflammatory process in IL-17 F knockout, DSS-induced colitis have been observed.Studying the correlation between innate and adaptive immune systems, we hope to obtain a focused reviewin order to facilitate future approaches aimed at elucidating the immunological mechanisms that control gut inflammation.