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.

Loss of interstitial cells of Cajal network in severe idiopathic gastroparesis

AIM: To report a case of severe idiopathic gastroparesis in complete absence of Kit-positive gastric interstitial cells of Cajal (ICC). METHODS: Gastric tissue from a patient with severe idiopathic gastroparesis unresponsive to medical treatment and requiring surgery was analyzed by conventional histology and immunohistochemistry. RESULTS: Gastric pacemaker cells expressing Kit receptor had completely disappeared while the local level of stem cell factor, the essential ligand for its development and maintenance, was increased. No signs of cell death were observed in the pacemaker region. CONCLUSION: These results are consistent with the hypothesis that a lack of Kit expression may lead to impaired functioning of ICC. Total gastrectomy proves to be curative.

Gastroparesis:New insights into an old disease

Gastroparesis(Gp)is a chronic disease characterized by a delayed gastric emptying in the absence of mechanical obstruction.Although this condition has been reported in the literature since the mid-1900s,only recently has there been renewed clinical and scientific interest in this disease,which has a potentially great impact on the quality of life.The aim of this review is to explore the pathophysiological,diagnostic and therapeutical aspects of Gp according to the most recent evidence.A comprehensive online search for Gp was carried out using MEDLINE and EMBASE.Gp is the result of neuromuscular abnormalities of the gastric motor function.There is evidence that patients with idiopathic and diabetic Gp may display a reduction in nitrergic inhibitory neurons and in interstitial cells of Cajal and/or telocytes.As regards diagnostic approach,99-Technetium scintigraphy is currently considered to be the gold standard for Gp.Its limits are a lack of standardization and a mild risk of radiation exposure.The C13 breath testing is a valid and safe alternative method.13C acid octanoic and the 13C Spirulina platensis recently approved by the Food and Drug Administration are the most commonly used diagnostic kits.The wireless motility capsule is a promising technique,but its use is limited by costs and scarce availability in many countries.Finally,therapeutic strategies are related to the clinical severity of Gp.In mild and moderate Gp,dietary modification and prokinetic agents are generally sufficient.Metoclopramide is the only drug approved by the Food and Drug Administration for Gp.However,other older and new prokinetics and antiemetics can be considered.As a second-line therapy,tricyclic antidepressants and cannabinoids have been proposed.In severe cases the normal nutritional approach can be compromised and artificial nutrition may be needed.In drug-unresponsive Gp patients some alternative strategies(endoscopic,electric stimulation or surgery)are available.

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.

Normal aspects of colorectal motility and abnormalities in slow transit constipation

Human colonic motility is a relatively difficult topic to investigate. However, the refinement of manometric techniques in recent years enabled us to study both the proximal and distal segments of the viscus. The present paper reviews our knowledge about normal aspects of colorectal motility in man and the abnormalities found in slow transit constipation (STC), one of the most frequent and difficult to treat subtypes of constipation. An internetbased search strategy of the Medline and Science Citation Index was performed using the keywords colon, colonic, colorectal, constipation, slow transit, motility, rectal, rectum in various combinations with the Boolean operators AND, OR and NOT. Only articles related to human studies were used, and manual cross-referencing was also performed. Most of colonic motor activity is represented by single nonpropagated contractions, rarely organized in bursts; this activity is maximal during the day, especially after waking and following meals. In addition, a specialized propagated activity with propulsive features is detectable, represented by high-and low-amplitude propagated contractions. In the severe form of constipation represented by the slow transit type, the above motor activity is completely deranged. In fact, both basal segmental activity (especially in response to meals) and propagated activity (especially that of high amplitude) are usually decreased, and this may represent a physiologic marker of this disorder. Human colonic motor activity is quite a complex issue, still only partly understood and investigated, due to anatomic and physiological difficulties. In recent years, however, some more data have been obtained, even in proximal segments. These data have helped in elucidating, although only in part, some pathophysiological mechanisms of chronic constipation, and especially of the STC subtype.

Understanding and treating refractory constipation

Chronic constipation is a frequently encountered disorder in clinical practice. Most constipated patients benefit from standard medical approaches. However, current therapies may fail in a proportion of patients. These patients deserve better evaluation and thorough investigations before their labeling as refractory to treatment. Indeed, several cases of apparent refractoriness are actually due to misconceptions about constipation, poor basal evaluation (inability to recognize secondary causes of constipation, use of constipating drugs) or inadequate therapeutic regimens. After a careful reevaluation that takes into account the above factors, a certain percentage of patients can be defined as being actually resistant to first-line medical treatments. These subjects should firstly undergo specific diagnostic examination to ascertain the subtype of constipation. The subsequent therapeutic approach should be then tailored according to their underlying dysfunction. Slow transit patients could benefit from a more robust medical treatment, based on stimulant laxatives (or their combination with osmotic laxatives, particularly over the short-term), enterokinetics (such as prucalopride) or secretagogues (such as lubiprostone or linaclotide). Patients complaining of obstructed defecation are less likely to show a response to medical treatment and might benefit from biofeedback, when available. When all medical treatments prove to be unsatisfactory, other approaches may be attempted in selected patients (sacral neuromodulation, local injection of botulinum toxin, anterograde continence enemas), although with largely unpredictable outcomes. A further although irreversible step is surgery (subtotal colectomy with ileorectal anastomosis or stapled transanal rectal resection), which may confer some benefit to a few patients with refractoriness to medical treatments.

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.

Non-surgical treatment of esophageal achalasia

Esophageal achalasia is an infrequent motility disorder characterized by a progressive stasis and dilation of the oesophagus; with subsequent risk of aspiration, weight loss, and malnutrition. Although the treatment of achalasia has been traditionally based on a surgical approach, especially with the introduction of laparoscopic techniques, there is still some space for a medical approach. The present article reviews the non-surgical therapeutic options for achalasia.

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.

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.

Toward a definition of colonic inertia

Chronic constipation is a relatively frequent symptom; among its subtypes, the so called-colonic inertia represents a disease condition that is often considered for surgery. However, to date, there has been no agreement on definition of colonic inertia, and a literature review showed that this definition was given to numerous entities that differ from each other.In this paper these concepts are reviewed and a more stringent definition of colonic inertia is proposed.

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.

Bio-feedback treatment of fecal incontinence: Where are we, and where are we going?

Fecal incontinence is a disabling disease, often observed in young subjects, that may have devastating psycho-social consequences. In the last years, numerous evidences have been reported on the efficacy of bio-feedback techniques for the treatment of this disorder. Overall, the literature data claim a success rate in more than 70% of cases in the short term. However, recent controlled trials have not confirmed this optimistic view, thus emphasizing the role of standard care. Nonetheless, many authors believe that this should be the first therapeutic approach for fecal incontinence due to the efficacy, lack of side-effects,and scarce invasiveness. Well-designed randomized,controlled trial are eagerly awaited to solve this therapeutic dilemma.

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.

Appropriateness of colonoscopy: Diagnostic yield and safety in guidelines

AIM: To evaluate if the guidelines for the appro-priateness of performing colonoscopy by American Society for Gastrointestinal Endoscopy (AGSE) and Italian Society of Digestive Endoscopy (SIED) yield a good diagnostic efficacy and do not present risks of missing important colonic pathologies in an Italian population sample.METHODS: A total of 1017 consecutive patients (560 men and 457 women; mean age 64.4 ± 16 years) referred to an open-access endoscopy unit for colonoscopy from July 2004 to May 2006 were evaluated according to ASGE and SIED guidelines for appropriateness of performing the procedure. Diagnostic yield was defined as the percentage of relevant colonic pathologies of the total number of colonoscopies performed.RESULTS: About 85.2% patients underwent colono-scopy that was considered appropriate based on at least one ASGE or SIED criterion, while it was considered inappropriate for 14.8% of patients. The diagnostic yield of colonoscopy was significantly higher for appropriate colonoscopies (26.94% vs 10.6%, P < 0.001) than for inappropriate colonoscopies (5.3%). There was no missed colorectal cancer following the ASGE/SIED criteria.CONCLUSION: ASGE/SIED guidelines have shown a good diagnostic yield and the rate of missing relevant colonic pathologies seems very low. Unfortunately, the percentage of inappropriate referrals for colonoscopy in an open-access endoscopy system is still high, despite the number of papers published on the issue and the definition of international guidelines. Further steps are required to update and standardize the guidelines to increase their diffusion and to promote educational programs for general practitioners.

Pathophysiological aspects of diverticular disease of colon and role of large bowel motility

Colonic diverticular disease (diverticulosis) is one of the most common gastrointestinal disorders in Western countries. This disorder is strictly related to aging and fibre intake, and still bears a discrete amount of morbidity. Numerous etiological co-factors have to date been implicated in the pathogenesis of the disease, yet the supporting evidence is still far from absolute. The present review considers the pathophysiology of colonic diverticular disease, with a special emphasis on factors related to abnormal colonic motility.

Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases

Clostridioides difficile(C.difficile)is progressively colonizing humans and animals living with humans.During this process,hypervirulent strains and mutated toxin A and B of C.difficile(TcdA and TcdB)are originating and developing.While in healthy subjects colonization by C.difficile becomes a risk after the use of antibiotics that alter the microbiome,other categories of people are more susceptible to infection and at risk of relapse,such as those with inflammatory bowel disease(IBD).Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma(CKs).Therefore,in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C.difficile infection and its progression and relapses.TcdB is internalized in the cell via three receptors:chondroitin sulphate proteoglycan 4;poliovirus receptor-like 3;and Wnt receptor frizzled family.Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types,while poliovirus receptor-like 3 induces only necrosis.It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis.Therefore,in subjects with IBD there are the conditions:(1)For greater susceptibility to C.difficile infection,such as the inflammatory state,and abnormalities of the microbiome and of the immune system;(2)for the enhancement of the cytotoxic activity of TcdB+Cks;and(3)for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis.The only therapeutic approach currently possible in IBD patients is monitoring of C.difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins.The future perspective is to generate bacteriophages against C.difficile for targeted therapy.

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.