Gastrointestinal endoscopy biopsy derived proteomic patterns predict indeterminate colitis into ulcerative colitis and Crohn’s colitis

Patients with indeterminate colitis (IC) are significantly younger at diagnosis with onset of symptoms before the age of 18 years with significant morbidity in the interim. The successful care of IC is based on microscopic visual predict precision of eventual ulcerative colitis (UC) or Crohn’s colitis (CC) which is not offered in 15%-30% of inflammatory bowel disease (IBD) patients even after a combined state-of-the-art classification system of clinical, visual endoscopic, radiologic and histologic examination. These figures have not changed over the past 3 decades despite the introduction of newer diagnostic modalities. The patient outcomes after restorative proctocolectomy and ileal pouch-anal anastomosis may be painstaking if IC turns into CC. Our approach is aiming at developing a single sensitive and absolute accurate diagnostic test tool during the first clinic visit through endoscopic biopsy derived proteomic patterns. Matrix-assisted-laser desorption/ionization mass spectrometry (MS) and/or imaging MS technologies permit a histology-directed cellular test of endoscopy biopsy which identifies phenotype specific proteins, as biomarker that would assist clinicians more accurately delineate IC as being either a UC or CC or a non-IBD condition. These novel studies are underway on larger cohorts and are highly innovative with significances in differentiating a UC from CC in patients with IC and could lend mechanistic insights into IBD pathogenesis.     

Lansoprazole-associated collagenous colitis： Diffuse mucosal cloudiness mimicking ulcerative colitis

There have only been a few reports on lansoprazole-associated collagenous colitis. Colonic mucosa of collagenous colitis is known to be endoscopically normal. We present a case of collagenous colitis where the mucosa showed diffuse cloudiness mimickin gulcerative colitis. A 70-year-old woman developed watery diarrhea four to nine times a day. She had interstitial pneumonia at 67 and reflux esophagitis at 70 years. Lansoprazole 30 mg/d had been prescribed for reflux esophagitis for nearly 6 mo. Lansoprazole was withdrawn due to its possible side effect of diarrhea. Colonoscopy disclosed diffuse cloudiness of the mucosa which suggested ulcerative colitis.Consequently sulfasalazine 2 g/d was started. The patient＇s diarrhea dramatically disappeared on the following day. However, biopsy specimens showed subepithelial collagenous thickening and infiltration of inflammatory cells in the lamina propria, confirming the diagnosis of collagenous colitis. One month after sulfasalazine therapy was initiated, colonoscopic and histological abnormalities resolved completely. Fivemonths later the diarrhea recurred. The findings on colonoscopy and histology were the same as before, confirming a diagnosis of collagenous colitis relapse. We found that the patient had begun to take lansoprazole again 3 mo ahead of the recent diarrhea.Withdrawal of lansoprazole promptly resolved the diarrhea. Endoscopic and histological abnormalities were also completely resolved, similar to the first episode. Retrospectively, the date of commencement of sulfasalazine and discontinuation of lansoprazole in the first episode was found to be the same. We conclude that this patient had lansoprazole-associated collagenous colitis.     

Clear cell colitis： A form of microscopic colitis in children

AIM： TO describe a new clinical and pathological subtype of microscopic colitis in children.
METHODS： A selected group of children with abdominal pain, constipation and/or diarrhoea showing discrete or no macroscopic abnormalities on endoscopy was described.
RESULTS： Multiple biopsies of colon showed large mononuclear clear cells in lamina propria of mucous membrane provided that good quality histological sections were performed and observed under a higher magnification. Otherwise, they could be misinterpreted as artefacts. Their presence in routine histology might suggest a systemic storage disease （Whipple＇s disease）, and neuronal intestine dysplasia. Using immunohistochemical staining and electron microscopy we confirmed their origin from CD68 positive mononuclear macrophages.
CONCLUSION： The presence of large clear cells is a constant microscopic feature. Failure of transient large bowel stationary macrophages plays a role in the pathogenesis of this benign microscopic clear cell colitis, sometimes coexisting with allergy.     

Diversion colitis: a trigger for ulcerative colitis in the in-stream colon?

The aetiology of ulcerative colitis is unknown. Two patientswithout pre-existing inflammatory bowel disease in whom end colostomy for faecal incontinence was complicated by diversion colitis in thedefunctioned rectosigmoid colon, are described. In both instances, colitis with the clinical, colonoscopic, and microscopic features ofulcerative colitis developed about a year later in the previously normal in-stream colon proximal to the colostomy. These cases suggestthat diversion colitis may be a risk factor for ulcerative colitis inpredisposed individuals and that ulcerative colitis can be triggered byanatomically discontinuous inflammation elsewhere in the large intestine.

Keywords:ulcerative colitis, diversion colitis

     

Drug therapy for ulcerative colitis

Ulcerative colitis (UC) is an inflammatory destructive diseaseof the large intestine occurred usually in the rectum andlower part of the colon as well as the entire colon.Drugtherapy is not the only choice for UC treatment and medicalmanagement should be as a comprehensive whole.Azulfidine,Asacol,Pentasa,Dipentum,and Rowasa allcontain 5-aminosalicylic acid (5-ASA),which is the topicalanti-inflammatory ingredient.Pentasa is more commonlyused in treating Crohn's ileitis because Pentasa capsulesrelease more 5-ASA into the small intestine than Asacoltablets.Pentasa can also be used for treating mild tomoderate UC.Rowasa enemas are safe and effective intreating ulcerative proctitis and proctosigmoiditis.The sulfa-free 5-ASA agents (Asacol,Pentasa,Dipentum andRowasa) have fewer side effects than sulfa-containingAzulfidine.In UC patients with moderate to severe diseaseand in patients who failed to respond to 5-ASA compounds,systemic (oral) corticosteroids should be used.Systemiccorticosteroids (prednisone,prednisolone,cortisone,etc.)are potent and fast-acting drugs for treating UC,Crohn'sileitis and ileocolitis.Systemic corticosteroids are noteffective in maintaining remission in patients with UC.Serious side effects can result from prolonged corticosteroidtreatment.To minimize side effects,corticosteroids shouldbe gradually reduced as soon as the disease remission isachieved.In patients with corticosteroid-dependent orunresponsive to corticosteroid treatment,surgery orirnmunomodulator is considered.Irnmunomodulatorsused for treating severe UC include azathioprine/6-MP,methotrexate,and cyclosporine.Integrated traditionalChinese and Western medicine is safe and effective inmaintaining remission in patients with UC.     

Refractory ulcerative colitis accompanied with cytomegalovirus colitis and multiple liver abscesses： A case report

Various hepato-biliary complications are an increased incidence in patients with inflammatory bowel disease, and portal bacteremia is well documented in patients with ulcerative colitis (DC). However, few reports mention UC in association with liver abscesses. Recently, there are several reports describing cytomegalovirus (CMV) infection in association with disease exacerbation and steroid refractoriness in patients with UC. Here we present a case of refractory UC accompanied with multiple liver abscesses and CMV colitis. The patient, a 72-year-old male, with a five-year history of repeated admissions to our hospital for UC, presented with an exacerbation of his UC. Sigmoidoscopy performed on admission suggested that his UC was exacerbated, then he was given prednisolone and mesalazine orally, and betamethasone enemas. However, he had exacerbated symptoms. Repeat Sigmoidoscopy revealed multiple longitudinal ulcers and pseudopolyps in the rectosigmoid colon. Although immunohistochemical staining of biopsy specimens and the serum testing for antigenemia were negative on admission and after the repeat Sigmoidoscopy, they became histologically positive for CMV. Nonetheless, the patient developed spiking fevers, soon after ganciclovir was administered. Laboratory studies revealed an increased white cell count with left shift, and Enterococcus fecalis grew in blood cultures. An abdominal computed tomography (CT) scan was obtained and the diagnosis of liver abscesses associated with UC was made, based on CT results. The hepatic abscesses were successfully treated with intravenous meropenem for 6 wk, without further percutaneous drainage. To our knowledge, this is the first reported case of multiple liver abscesses that develop during UC exacerbation complicated by CMV colitis.     

Fulminant gangrenous ischemic colitis: is it the solely severe type of ischemic colitis?

Purpose

The purposes of the study are to evaluate the characteristics of gangrenous colitis and to identify clinicobiological factors.

Methods

We performed a retrospective study of 75 patients in whom the diagnosis was made endoscopically and confirmed pathologically, between March 2004 and March 2010 at a tertiary teaching hospital. We classified ischemic colitis into the reversible and irreversible types (gangrenous colitis). The influence of factors, such as medical history, symptoms, physical examination, laboratory abnormalities, endoscopic findings, abnormalities on computed tomography, perioperative issues, complications, and several scoring systems, on gangrenous ischemic changes and mortality was evaluated by univariate and multivariate analyses.

Results

Ischemic colitis was classified as gangrenous ischemic type in 19 patients. The sigmoid colon was the most common site of involvement. However, the disease distribution was significantly different between the two groups. Pancolitis was most commonly observed for fulminant gangrenous colitis. A difference between the two groups was detected for several factors: age, mortality, physiologic score, APACHE II, mean arterial pressure at the time of admission, heart rate, albumin level, and sodium bicarbonate concentration. Multivariate analysis indicated four factors predictive of gangrenous colitis: absence of hematochezia, abdominal tenderness, absence of diarrhea, and albumin level. Another multivariate analysis excluding gangrenous change factors for mortality indicated four factors: arterial pH, serum sodium bicarbonate (metabolic acidosis), albumin (<3.0), and arterial oxygenation.

Conclusion

Absence of diarrhea and hematochezia, presence of abdominal tenderness, and hypoalbuminemia could be the predictors for development of gangrenous changes of ischemic colitis.

     

Immunologic “colitis” in dogs

Summary Dog colon mucosal extracts are antigenic to rabbits. After several months of an immunization program with adjuvant, antibodies are demonstrable by gel diffusion and increased precipitin titers. When this anti-dog-colon-rabbit serum is given intravenously to recipient dogs, an acute immunologic reaction develops, primarily limited to the colon, but with evidence of systemic participation. In 24 hours this is characterized by mucosal hemorrhage and focal necrosis, leukocytic infiltration most marked at the base of crypts, submucosal edema, venous dilatation, and perivascular cuffing. This reaction requires further investigation for understanding of its mechanism and significance.Paper prepared with the technical assistance of Samuel McQueen, M.D., and Albert Jones, B.S., both Student Fellows, National Science Foundation, and Gene Lawyer, B.S., Student Research Fellow, U. S. Public Health Service.We wish to make grateful acknowledgement of the encouragement, advice, and assistance given us by Drs. E. H. Storer, Anna Dulaney, and A. J. Cummins, all of the University of Tennessee College of Medicine.     

Segmental colitis: so what?

The existence of chronic mucosal inflammation, confined to sigmoid colons that bear diverticula, is termed 'segmental colitis'. This condition often mimicks inflammatory bowel disease at histological examination. The observed rectal sparing suggests a possible form of Crohn's disease, but no other similarities between segmental colitis and Crohn's colitis are detectable. Medical treatment for segmental colitis, empirically carried out with drugs such as sulfasalazine and mesalazine, is mostly successful and, when surgery is required, post-operative recurrences are infrequent. Although the existence of segmental colitis as a true clinical entity remains questionable, it appears unlikely that this condition represents an atypical form of inflammatory bowel disease.     

Lymphocytic colitis: a distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis

BACKGROUND AND AIMS: It is not known whether lymphocytic colitis and collagenous colitis represent different clinical entities or constitute part of a spectrum of disease. METHODS: Detailed clinical features and histological findings were compared in a large series of patients with confirmed lymphocytic and collagenous colitis. RESULTS: Histological diagnosis was confirmed in 96 patients with collagenous colitis and 80 with lymphocytic colitis. Twenty eight per cent of patients with collagenous colitis and 26% of patients with lymphocytic colitis had overlapping but less pronounced histological features. Both groups were equal in terms of age, use of aspirin and non-steroidal anti-inflammatory drugs, associated autoimmune conditions, arthritis, diarrhoea, and abdominal pain. The male:female ratio was 27:73 for collagenous colitis and 45:55 for lymphocytic colitis (p=0.013). Twenty five per cent of patients with collagenous colitis compared with 14% of patients with lymphocytic colitis were active smokers; only 8.3% of patients with collagenous colitis had stopped smoking compared with 23% of patients with lymphocytic colitis (p=0.013). Drug induced disease was suspected for ticlopidine (two collagenous colitis, four lymphocytic colitis) and flutamide (four lymphocytic colitis). Mean duration of symptoms before diagnosis was two months for lymphocytic colitis and four months for collagenous colitis. Overall prognosis was generally mild; 84% of patients with lymphocytic colitis and 74% of patients with collagenous colitis reported resolution or significant improvement (p=0.033). CONCLUSIONS: Collagenous and lymphocytic colitis are similar but not identical. Patients with lymphocytic colitis present somewhat earlier and are less likely to be active smokers. Symptoms are milder and more likely to disappear in lymphocytic colitis. Ticlopidine and flutamide should be added to the list of drugs inducing colitis.     

Myo-inositol reduces β-catenin activation in colitis

AIM To assess dietary myo-inositol in reducing stem cell activation in colitis,and validate pβ-cateninS~(552) as a biomarker of recurrent dysplasia.METHODS We examined the effects of dietary myo-inositol treatment on inflammation,pβ-cateninS~(552) and p Akt levels by histology and western blot in IL-10-/-and dextran sodium sulfate-treated colitic mice. Additionally,we assessed nuclear pβ-cateninS~(552) in patients treated with myo-inositol in a clinical trial,and in patients with and without a history of colitis-induced dysplasia.RESULTS In mice,pβ-cateninS~(552) staining faithfully reported the effects of myo-inositol in reducing inflammation and intestinal stem cell activation. In a pilot clinical trial of myo-inositol administration in patients with a history of low grade dysplasia(LGD),two patients had reduced numbers of intestinal stem cell activation compared to the placebo control patient. In humans,pβ-cateninS~(552) staining discriminated ulcerative colitis patients with a history of LGD from those with benign disease.CONCLUSION Enumerating crypts with increased numbers of pβ-cateninS~(552)-positive cells can be utilized as a biomarker in colitis-associated cancer chemoprevention trials.     

Manipulation of enteric flora in ulcerative colitis

TO THE EDITOR Reviewing the available therapeutic options in the medical treatment of ulcerative colitis,Xu et al., have omitted to mention an important aspect in the pharmacological management of the disease, namely the possibility to promote clinical and endoscopic improvement by manipulating the enteric flora.     

Is "ischemic" colitis ischemic?

Ischemic colitis appears to be a collection of diseases rather than a single entity. On the one hand, there is the colitis that truly appears to be caused by a lack of blood flow and, on the other hand, there is the disease that is called "ischemic" for lack of a better diagnosis-the colitis that is more "idiopathic" than "ischemic." Four widely held tenets of "ischemic" colitis are wrong: 1) the colon is not particularly sensitive to ischemia; 2) ischemic colitis is rarely preceded by a period of global hypoperfusion; 3) the "watershed areas" are not disproportionately affected; and 4) colonoscopy with biopsy is not specific for the disease. The cause of "ischemic" colitis is unknown. Therefore it is, until proven otherwise, "acute idiopathic colitis."     

Endothelin and vascular remodelling in colitis pathogenesis—Appendicitis and appendectomy limit colitis by suppressing endothelin pathways

Purpose

Appendicitis and appendectomy(AA), when done at a young age, offer protection against inflammatory bowel disease (IBD) development in later life. However, IBD pathogenesis involves both immunological and vascular abnormalities. Using the first murine model of AA (developed by us), we aimed to determine the role of AA in modulating vascular remodelling mediated by endothelin activity in IBD.

Methods

Mice with two laparotomies each served as controls (sham-sham or SS). Distal colons were harvested (four AA group colons, four SS group colons), and RNA extracted from each. The RNA was subjected to microarray analysis and RT-PCR validation. Gene set enrichment analysis (GSEA) software was used to further analyze the microarray data.

Results

Gene expression of seven genes closely associated with endothelin activity was examined in distal colons 3 days post-AA and 28 days post-AA. While there were no gene expression changes 3 days post-AA, the genes EDN1 (0.7-fold), EDN2 (0.8-fold) and ECE2 (0.8-fold) were downregulated (*p value <0.05) 28 days post-AA. However, EDN3 (1.3-fold) was upregulated 28 days post-AA (*p value <0.05). GSEA analysis showed downregulation of 11 gene sets (stringent cut-offs—false discovery rate <5 % and p value <0.001) associated with endothelin and endothelin-converting enzyme genes by AA, in contrast to only 1 being upregulated.

Conclusions

AA induces a delayed but significant suppression of genes pertaining to endothelin activity. Elucidating the pathways involved in suppression of endothelin activity and manipulation of different genes/enzymes/proteins related to endothelin activity will significantly enhance the extant repertoire of therapeutic options in IBD.