Pathophysiology, Evaluation, and Management of Chronic Watery Diarrhea.

Chronic watery diarrhea poses a diagnostic and therapeutic challenge and is often a disabling condition for patients. Although acute diarrhea is likely to be caused by infection, the causes of chronic diarrhea (>4 weeks in duration) are more elusive. We review the pathophysiology, diagnosis, and treatment of chronic diarrhea. Drawing on recent insights into the molecular mechanisms of intestinal epithelial transport and barrier function, we discuss how diarrhea can result from a decrease in luminal solute absorption, an increase in secretion, or both, as well as derangements in barrier properties. We also describe the various extraepithelial factors that activate diarrheal mechanisms. Finally, clinical evaluation and tests used in the assessment of patients presenting with chronic diarrhea are reviewed, and an algorithm guiding therapeutic decisions and pharmacotherapy is presented.

Chronic Diarrhea: Diagnosis and Management.

Chronic diarrhea is a common problem affecting up to 5% of the population at a given time. Patients vary in their definition of diarrhea, citing loose stool consistency, increased frequency, urgency of bowel movements, or incontinence as key symptoms. Physicians have used increased frequency of defecation or increased stool weight as major criteria and distinguish acute diarrhea, often due to self-limited, acute infections, from chronic diarrhea, which has a broader differential diagnosis, by duration of symptoms; 4 weeks is a frequently used cutoff. Symptom clusters and settings can be used to assess the likelihood of particular causes of diarrhea. Irritable bowel syndrome can be distinguished from some other causes of chronic diarrhea by the presence of pain that peaks before defecation, is relieved by defecation, and is associated with changes in stool form or frequency (Rome criteria). Patients with chronic diarrhea usually need some evaluation, but history and physical examination may be sufficient to direct therapy in some. For example, diet, medications, and surgery or radiation therapy can be important causes of chronic diarrhea that can be suspected on the basis of history alone. Testing is indicated when alarm features are present, when there is no obvious cause evident, or the differential diagnosis needs further delineation. Testing of blood and stool, endoscopy, imaging studies, histology, and physiological testing all have roles to play but are not all needed in every patient. Categorizing patients after limited testing may allow more directed testing and more rapid diagnosis. Empiric antidiarrheal therapy can be used to mitigate symptoms in most patients for whom a specific treatment is not available.

Gastro 2013 APDW/WCOG Shanghai working party report: chronic diarrhea: definition, classification, diagnosis.

Diarrhea is best defined as passage of loose stools often with more frequent bowel movements. For clinical purposes, the Bristol Stool Form Scale works well to distinguish stool form and to identify loose stools. Laboratory testing of stool consistency has lagged behind. Acute diarrhea is likely to be due to infection and to be self-limited. As diarrhea becomes chronic, it is less likely to be due to infection; duration of 1 month seems to work well as a cut-off for chronic diarrhea, but detailed scientific knowledge is missing about the utility of this definition. In addition to duration of diarrhea, classifications by presenting scenario, by pathophysiology, and by stool characteristics (e.g. watery, fatty, or inflammatory) may help the canny clinician refine the differential diagnosis of chronic diarrhea. In this regard, a careful history remains the essential part of the evaluation of a patient with diarrhea. Imaging the intestine with endoscopy and radiographic techniques is useful, and biopsy of the small intestine and colon for histological assessment provides key diagnostic information. Endomicroscopy and molecular pathology are only now being explored for the diagnosis of chronic diarrhea. Interest in the microbiome of the gut is increasing; aside from a handful of well-described infections because of pathogens, little is known about alterations in the microbiome in chronic diarrhea. Serological tests have well-defined roles in the diagnosis of celiac disease but have less clearly defined application in autoimmune enteropathies and inflammatory bowel disease. Measurement of peptide hormones is of value in the diagnosis and management of endocrine tumors causing diarrhea, but these are so rare that these tests are of little value in screening because there will be many more false-positives than true-positive results. Chemical analysis of stools is of use in classifying chronic diarrhea and may limit the differential diagnosis that must be considered, but interpretation of the results is still evolving. Breath tests for assessment of carbohydrate malabsorption, small bowel bacterial overgrowth, and intestinal transit are fraught with technical limitations that decrease sensitivity and specificity. Likewise, tests of bile acid malabsorption have had limited utility beyond empirical trials of bile acid sequestrants.

Disability in inflammatory bowel disease.

Disability can include different aspects of patient's quality of life from physical to psychosocial to employment. Disability in IBD patients contributes to loss of workplace personnel, increased sick leave, and other indirect costs to society. Considerations for more expensive treatment regimens should include their potential to reduce indirect costs to the individual patients and to society in general. The recently developed tool could help establish specific criteria in a set of these diseases that have varied effects and severity.

The promise and pitfalls of serologic testing in inflammatory bowel disease.

The role of IBD serologies is still evolving. However, as that evolution progresses, it will continue to provide important insights into the etiology of IBD and help define individualized treatment strategies for patients. The presence of multiple IBD antimicrobial antibodies and increased reactivity form a useful heuristic model to understand the evolution of CD. The role of ANCAs and autoantibodies in pathogenesis of UC is an area that requires further investigation. Although IBD serologies exhibit considerable diagnostic accuracy, it is unclear whether they will supplant simpler and more direct evaluations in making an initial diagnosis of UC or Crohn (Table 3). The utility of panels of IBD serologies to stratify and predict the course of CD has been an arena of fertile investigation. Developing individual treatment strategies based on the probability of developing complicated aggressive disease would be a significant advance in medical management of CD. However, if major clinical decisions are to be made based on these serologies, we will need more prospective critical studies from the time of diagnosis to define their clinical applicability and to demonstrate a true difference in outcomes.

Drug-induced, factitious, & idiopathic diarrhoea.

The aetiology of diarrhoea can often be simple to identify, but in some cases may pose a challenge. The diagnosis of drug-induced diarrhoea can easily be sorted based on timing of the symptom with onset of a new drug. Treatment can vary from simply monitoring and eventual resolution with continuation of the drug, to discontinuation of the offending agent. In cases where a drug cannot always be stopped, additional medications can help control the symptom. Factitious diarrhoea can present a diagnostic challenge if the evaluating physician does not suspect its possibility. Typically a careful history, and in some cases, stool testing can provide clues. The diagnosis of idiopathic diarrhoea is often made when exhaustive testing provides no definite aetiology and the goal of management is supportive care and symptomatic treatment.

Suppression of aberrant transient receptor potential cation channel, subfamily V, member 6 expression in hyperproliferative colonic crypts by dietary calcium.

Dietary calcium is believed to reduce colon cancer risk, but the mechanism by which this occurs is poorly understood. Employing the Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model, we previously showed that a high-calcium diet (hCa) significantly abrogated hyperplasia in the distal colons of NIH-Swiss mice. Here, we explored the mechanism of dietary protection by hCa by analyzing the expression of genes involved in the regulation of Ca uptake/flux in the intestinal epithelium, including the Ca-sensing receptor, vitamin D receptor, Ca binding protein, and transient receptor potential cation channels, subfamily V, members 5 and 6 (TRPV5/6). Interestingly, while TRPV6 expression increased significantly during TMCH, the expression of the other gene products was unchanged. This elevated TRPV6 expression was significantly abrogated by a hCa diet. Immunofluorescence revealed apical membrane localization of TRPV6 in the normal colon, whereas during TMCH we observed intense apical pole and cytoplasmic staining along the entire longitudinal crypt axis, including the expanded proliferating zone. The hCa diet reversed this effect. In humans, overexpression of TRPV6 was associated with early-stage colon cancer, and in colon carcinoma cells, inhibition of TRPV6 expression by small interfering RNA inhibited their proliferation and induced apoptosis. TRPV6 small interfering RNA also diminished the transcriptional activity of the calcium-dependent nuclear factors in activated T cells. Thus the aberrant overexpression of TRPV6 contributes to colonic crypt hyperplasia in mice and to colon cancer cell proliferation in humans. Therefore, it is likely that suppression of TRPV6 by a hCa diet is required for its protective effects in the colon.

Diabetic diarrhea.

Diabetic patients with diarrhea may present clinical challenges in diagnosis and treatment. Particular diagnoses are more prevalent in diabetic patients than in the general population. Medications are often a culprit for chronic diarrhea, and the medication list should always be carefully scrutinized for those with diarrhea as a side effect. In diabetic patients, metformin is a common cause of diarrhea. Diabetic patients are more likely to have associated diseases (eg, celiac sprue and microscopic colitis) that present with diarrhea as the sole complaint. Ingested sugar-free foods that may contain sorbitol or other agents can cause diarrhea in diabetic patients. Finally, diabetic enteropathy can itself cause diarrhea. The various etiologies can be diagnosed with a thorough history and appropriate diagnostic tests. This article focuses on the etiologies of diarrhea that are seen with higher incidence in diabetic patients.

beta-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia.

Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we provide mechanistic basis of changes in beta-catenin/APC/CKIepsilon leading to progression and/or regression of hyperplasia in vivo. In response to CR-induced TMCH, crypt lengths increased significantly between days 6-27 post-infection, followed by a steep decline by day 34. beta-Cat(45)/total beta-catenin were elevated on day 1 post-infection, preceding changes in crypt length, and persisted for 27 days before declining by day 34. Importantly, cellular CKIepsilon and beta-catenin co-immunoprecipitated and exhibited remarkable parallel changes in kinetics during hyperplasia/regression phases. beta-catenin, phosphorylated at Ser33,37 and Thr41 (beta-cat(33,37/41)), was low till day 12, followed by gradual increase until day 27 before declining by day 34. GSK-3beta exhibited significant Ser(9)-phosphorylation/inactivation at days 6-12 with partial recovery at days 27-34. Wild type (wt) APC (p312) levels increased at day 6 with transient proteolysis/truncation to p130 form between days 12 and 15; p312 reappeared by day 19 and returned to baseline by day 34. The kinetics of beta-Cat(45)/beta-catenin nuclear accumulation and acetylation (Ac-beta-Cat(Lys49)) from days 6 to 27, followed by loss of phosphorylation/acetylation by day 34 was almost identical; Tcf-4 co-immunoprecipitated with beta-Cat(45)/beta-catenin and localized immunohistochemically to beta-Cat(41/45)-positive regions leading to elevated cyclin D1 expression, during the hyperproliferative, but not regression phases of TMCH. CKIepsilon mediated phosphorylation of beta-Cat(45), resulting in stabilization/nuclear translocation of beta-Cat(45) may be critical for maintaining proliferation at days 6-27. Reversal of GSK-3beta phosphorylation and APC changes may be equally critical during the regression phase from days 27 to 34.

Therapy Insight: gastrointestinal complications of diabetes--pathophysiology and management.

Patients with diabetes often have gastrointestinal symptoms, but the extent and severity of this problem and the specificity of the symptoms are not nearly as well defined as frequently assumed. Any part of the gastrointestinal tract can be affected, and the presenting symptoms depend on the composite of dysfunctional elements. Gastroesophageal reflux, Candida esophagitis, gastroparesis, diarrhea and constipation are among the many common gastrointestinal complications of diabetes. No specific risk factor for the development of these complications has been identified and their etiology is most likely to be multifactorial, involving both reversible and irreversible processes. Treatment should be directed at tighter glycemic and symptom control, which can bring about clinical improvement for many patients. For other patients, however, effective clinical management is problematic because no therapies are available to prevent or correct the underlying disease mechanisms. Studies now suggest that reduced levels of key trophic factors cause transdifferentiation of pacemaker interstitial cells of Cajal into a smooth-muscle-like phenotype. If this really is the case, therapies directed at restoring the normal milieu of trophic signals could correct the dysfunction of the interstitial cells of Cajal and resolve many gastrointestinal complications. Advances in stem cell technology also hold promise to provide a cure for diabetes and to correct abnormalities in gastrointestinal pathology.

Drug-induced diarrhea.

Many drugs have been known to cause diarrhea, although their mechanism of action has not been well described. The gastrointestinal tract may become dysregulated when exposed to a drug that could disrupt mechanisms controlling mucosal permeability, transport, motility, and gut metabolism. This review examines the mechanism by which drugs induce diarrhea within the broad classification of watery, inflammatory, and fatty characteristics of the stool. Treatment may vary depending on this classification and usually includes withdrawal of the offending drug. However, in some cases, diarrhea may resolve with continued use or through nonspecific agents, such as Lomotil (Pfizer, New York, NY) or loperamide.