Slow transit constipation: A functional disorder becomes an enteric neuropathy

Slow transit constipation has been traditionally considered and classified as a functional disorder. However, clinical and manometric evidence has been accumulating that suggests how most of the motility alterations in STC might be considered of neuropathic type.In addition, further investigations showed that subtle alterations of the enteric nervous system, not evident to conventional histological examination, may be present in these patients. In the present article we will discuss these evidences, and will try to put them in relation with the abnormal motor function of the large bowel documented in this pathological condition.

Neurological disorders and inflammatory bowel diseases

Extraintestinal manifestations occur in about one-third of patients living with inflammatory bowel disease(IBD) and may precede the onset of gastrointestinal symptoms by many years. Neurologic disorders associated with IBD are not frequent, being reported in 3% of patients, but they often represent an important cause of morbidity and a relevant diagnostic issue. In addition, the increasing use of immunosuppressant and biological therapies for IBD may also play a pivotal role in the development of neurological disorders of different type and pathogenesis. Hence, we provide a complete and profound review of the main features of neurological complications associated with IBD, with particular reference to those related to drugs and with a specific focus on their clinical presentation and possible pathophysiological mechanisms.

Cellular and molecular basis of chronic constipation: Taking the functional/idiopathic label out

In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called "functional" or "idiopathic" disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable abnormalities). This is particularly true, for instance, for irritable bowel syndrome, the prototype entity of "functional" gastrointestinal disorders, where low-grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated. Thus, researchers have also investigated other functional/idiopathic gastrointestinal disorders, and found that some organic ground is present, such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia and mucosal immune activation and mild eosinophilia in functional dyspepsia. Here we show evidence, based on our own and other authors' work, that chronic constipation has several abnormalities reconductable to alterations in the enteric nervous system, abnormalities mainly characterized by a constant decrease of enteric glial cells and interstitial cells of Cajal (and, sometimes, of enteric neurons). Thus, we feel that (at least some forms of) chronic constipation should no more be considered as a functional/idiopathic gastrointestinal disorder, but instead as a true enteric neuropathic abnormality.

Enteric glial cells and their role in gastrointestinal motor abnormalities: Introducing the neuro-gliopathies

The role of enteric glial cells has somewhat changed from that of mere mechanical support elements, gluing together the various components of the enteric nervous system, to that of active participants in the complex interrelationships of the gut motor and inflammatory events. Due to their multiple functions, spanning from supporting elements in the myenteric plexuses to neurotransmitters, to neuronal homeostasis, to antigen presenting cells, this cell population has probably more intriguing abilities than previously thought. Recently, some evidence has been accumulating that shows how these cells may be involved in the pathophysiological aspects of some diseases. This review will deal with the properties of the enteric glial cells more strictly related to gastrointestinal motor function and the human pathological conditions in which these cells may play a role, suggesting the possibility of enteric neuro- gliopathies.

Novel oral-targeted therapies for mucosal healing in ulcerative colitis

Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing(MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.

Endoscopic mucosal resection for high-grade dysplasia and intramucosal carcinoma in Barrett's esophagus: An Italian experience

AIM： To evaluate endoscopic mucosal resection （EMR） in patients with high-grade dysplasia （HGD） and/or intramucosal cancer （IMC） in Barrett＇s esophagus （BE）. METHODS： Between June 2000 and December 2003, 39 consecutive patients with HGD （35） and/or IMC （4） underwent EMR. BE 〉30 mm was present in 27 patients. In three patients with short segment BE （25.0%）, HGD was detected in a normal appearing BE. Lesions had a mean diameter of 14.8＋10.3 ram. Mucosal resection was carried out using the cap method. RESULTS： The average size of resections was 19.7± 9.4×14.6＋8.2 mm. Histopathologic assessment postresection revealed 5 low-grade dysplasia （LGD） （12.8%）, 27 HGD （69.2%）, 2 IMC （5.1%）, and 5 SMC （-12.8%）. EMR changed the pre-treatment diagnosis in 10 patients （25.6%）. Three patients with SMC underwent surgery. Histology of the surgical specimen revealed 1 TON0 and 2 TIN0 lesions. The remaining two patients were cancer free at 32.5 and 45.6 mo, respectively. A metachronous lesion was detected after 25 mo in one patient with HGD. Intra-procedural bleeding, controlled at endoscopy, occurred in four patients （10.3%）. After a median follow-up of 34.9 mo, all patients remained in remission. CONCLUSION： In the medium term, EMR is effective and safe to treat HGD and/or IMC within BE and is a valuable staging method. It could become an alternative to surgery.

Gastrointestinal motility disorders in inflammatory bowel diseases

The relationship between motility and inflammatory gastrointestinal disorders is at the same time complex and intriguing since these conditions might share some genetic, environmental, immunological and microbial predisposing factors. In addition, significant symptom overlapping may occur, muddling the waters within the clinical context. Although on one hand this represents a challenge for the clinician for a potential under- or over-treatment and diagnostic delay, on the other hand it possibly represents an opportunity for the researcher to better disclose the intimate relationship between chronic (often low-grade) inflammation, motor disorders and deranged sensory function. The best example is probably represented by Crohn’s disease and ulcerative colitis. In fact, a number of gastrointestinal motor disorders have been described in association with these diseases, disorders which span from the esophagus to the anorectum, and which will be extensively covered in this review. It is conceivable that at least part of this derangement is strictly related to inflammatory cytokine trafficking and neuromuscular changes; however, given the high prevalence of functional gastrointestinal disorders in the general population, this overlap might also be serendipitous. However, it is worth noting that literature data on this topic are relatively scarce, sometimes quite outdated, and mostly focused on the interplay between irritable bowel syndrome and inflammatory bowel disease. Nevertheless, both researchers and clinicians must be aware that symptoms related to gastrointestinal motility disorders may be highly prevalent in both active and inactive inflammatory bowel disease, correlate with greater psychological comorbidity and poorer quality of life, and may negatively influence the therapeutic approaches.

Linear endoscopic ultrasonography vs magnetic resonance imaging in ampullary tumors

AIM:To assess linear endoscopic ultrasound (L-EUS) and magnetic resonance imaging (MRI) in biliary tract dilation and suspect small ampullary tumor.METHODS:L-EUS and MRI data were compared in 24 patients with small ampullary tumors;all with subsequent histological confirmation.Data were collected prospectively and the accuracy of detection,histological characterization and N staging were assessed retrospectivelyusing the results of surgical or endoscopic treatment as a benchmark.RESULTS:A suspicion of ampullary tumor was present in 75% of MRI and all L-EUS examinations,with 80% agreement between EUS and histological findings at endoscopy.However,L-EUS and histological TN staging at surgery showed moderate agreement (κ=0.54).CONCLUSION:L-EUS could be a useful adjunct as a diagnostic tool in the evaluation of patients with sus-pected ampullary tumors.

Histological healing in inflammatory bowel disease:A still unfulfilled promise

Treatment of inflammatory bowel disease(IBD) is traditionally based on several drugs,including salicylates,corticosteroids,and antibiotics;in addition,the therapeutic armamentarium has considerably evolved with the advent of newer,effective therapeutic measures(such as the biological agents) that are able to improve in a considerable manner both the clinical and endoscopic variables.Thus,mucosal healing,at least considered from an endoscopic point of view,is today regarded as the ultimate endpoint for treatment of these conditions.However,it is also increasingly clear that endoscopic healing is not necessarily paralleled by histological healing;There are few doubts that the latter should be considered as a true,objective healing and the ultimate goal to reach when treating patients with IBD.Unfortunately,and surprisingly,only a few,incomplete,and somewhat conflicting data exist on this topic,especially because there is still the need to standardize both histological assessment and the severity grading of these disorders;Issues that have not been yet been resolved for clinical practice and therapeutic trials.Hopefully,with the help of an increased awareness on the clinical researchers' side,and the availability of dedicated pathologists on the other side,this matter will be effectively faced and resolved in the near future.

Microscopic enteritis:Bucharest consensus

Microscopic enteritis(ME) is an inflammatory condition of the small bowel that leads to gastrointestinal symptoms,nutrient and micronutrient deficiency.It is characterised by microscopic or sub-microscopic abnormalities such as microvillus changes and enterocytic alterations in the absence of definite macroscopic changes using standard modern endoscopy.This work recognises a need to characterize disorders with microscopic and submicroscopic features,currently regarded as functional or non-specific entities,to obtain further understanding of their clinical relevance.The consensus working party reviewed statements about the aetiology,diagnosis and symptoms associated with ME and proposes an algorithm for its investigation and treatment.Following the 5th International Course in Digestive Pathology in Bucharest in November 2012,an international group of 21 interested pathologists and gastroenterologists formed a working party with a view to formulating a consensus statement on ME.A five-step agreement scale(from strong agreement to strong disagreement) was used to score 21 statements,independently.There was strong agreement on all statements about ME histology(95%-100%).Statements concerning diagnosis achieved 85% to 100% agreement.A statement on the management of ME elicited agreement from the lowest rate(60%) up to 100%.The remaining two categories showed general agreement between experts on clinical presentation(75%-95%) and pathogenesis(80%-90%) of ME.There was strong agreement on the histological definition of ME.Weaker agreement on management indicates a need for further investigations,better definitions and clinical trials to produce quality guidelines for management.This ME consensus is a step toward greater recognition of a significant entity affecting symptomatic patients previously labelled as non-specific or functional enteropathy.

Failed stapled rectal resection in a constipated patient with rectal aganglionosis

A rare case of a severely constipated patient with rectal aganglionosis is herein reported.The patient,who had no megacolon/megarectum,underwent a STARR,i.e.,stapled transanal rectal resection,for obstructed defecation,but her symptoms were not relieved.She started suffering from severe chronic proctalgia possibly due to peri-retained staples fibrosis.Intestinal transit times were normal and no megarectum/megacolon was found at barium enema.A diverting sigmoidostomy was then carried out,which was complicated by an early parastomal hernia,which affected stoma emptying.She also had a severe diverting proctitis,causing rectal bleeding,and still complained of both proctalgia and tenesmus.A deep rectal biopsy under anesthesia showed no ganglia in the rectum,whereas ganglia were present and normal in the sigmoid at the stoma site.As she refused a Duhamel procedure,an intersphincteric rectal resection and a refashioning of the stoma was scheduled.This case report shows that a complete assessment of the potential causes of constipation should be carried out prior to any surgical procedure.

Inflammatory bowel disease in the dog:Differences and similarities with humans

Inflammatory bowel diseases (IBD) represent important chronic conditions affecting the gastrointestinal tract in man.However,similar disorders are found in several animal species and the IBD affecting dogs are particularly important.These are encompassed by an umbrella of probably several different entities with common symptoms,some of which seem to share striking similarities with human conditions.This review will focus on the actual knowledge of IBD in dogs,and attempt to identify differences and similarities with human IBD conditions.

Is hyperhomocysteinemia relevant in patients with celiac disease?

AIM： TO investigate whether this might be related to the presence of hyperhomocysteinemia. METHODS： From January 1998 to December 2008, we evaluated the presence of hyperhomocysteinemia in a series of 165 adult celiac disease （CD） patients （138 females and 27 males, mean age 43 years）.RESULTS： Hyperhomocysteinemia was evident in 32 patients （19.3%）, although most of them had moderate levels （mean value 25 mcg/ml; range 15-30）. Only one patient had a history of myocardial infarction （heterozygosis for N5-N10-metil tetrahydrofolate reductase mutation）. CONCLUSION： The systematic assessment of hyperhomocysteinemia seems, at present, unjustified in CD patients.

Dysplasia in perforated intestinal pneumatosis complicating a previous jejuno-ileal bypass:A cautionary note

We present the case of an elderly woman who developed a bowel perforation related to pneumatosis intestinalis, 33 years after a jejuno-ileal bypass for severe obesity. Final histological examination revealed the presence of dysplasia in the resected specimen. On the basis of our case and a review of the literature, we discuss the etiopathogenesis, the clinical aspects and the treatment of this rare condition.

Inflammatory bowel disease:A proposal to facilitate the achievement of an unequivocal diagnosis

Following the international guidelines criteria an adequate"diagnostic conclusion"of inflammatory bowel disease(IBD)can be achieved only if clinical,endoscopic and laboratory findings,together with sample technical adequacy and unequivocal histomorphological signs of the disease are available.Thus,a conclusive diagnosis requires a complex combination of clinical, endoscopic and histological data.A considerable number of endoscopic biopsies obtained from IBD patients do not meet the above-mentioned requirements.The aim of the present proposal is to introduce a binary system of evaluation in the"diagnostic conclusion"of the histopathological report that will help to simplify the clinical decisions and consequent patient management.In patients with no history of disease,the pathologist should classify the biopsies in"Diagnostic",when the criteria established by the international guidelines are satisfied and"not diagnostic"when one or more of the above-mentioned criteria are not met. The term"not diagnostic"should replace"highly suggestive"and"probable".This new terminology could avoid ambiguous expressions that encourage the clinician to classify the patient as affected by IBD without fulfilling all of the requirements for an accurate diagnostic approach.

ntestinal-mucosa anti-transglutaminase antibody assays to test for genetic gluten intolerance

Celiac disease （CD） is an autoimmune enteropathy character- ized by gluten-triggered intestinal mucosa lesions in genetically susceptible individuals carrying the HLA DQ2 or DQ8. CD diagnosis is based on the concentration of IgA serum anti- transglutaminase （anti-tTG） antibodies together with mucosal damage at intestinal biopsy.