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.

Medical and surgical complications of inflammatory bowel disease in the elderly: a systematic review.

BACKGROUND/AIMS: The complications of therapy, hospitalization, and surgery related to inflammatory bowel disease (IBD) in the elderly are not well described. While multiple reviews have described the management and complications of elderly patients with IBD, none have been performed in a systematic fashion. METHODS: We performed a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to evaluate the association between elderly patients with IBD and complications from therapy, hospitalizations, and surgery. Eligible studies were identified via structured keyword searches in PubMed and manual literature searches. RESULTS: A total of 5,644 publications were identified. Of these, fourteen studies met inclusion criteria, encompassing 963 elderly IBD patients (113 Crohn's disease and 850 ulcerative colitis patients), over 37,000 hospitalizations of elderly IBD patients and over 4,500 controls. Consistent associations were observed between increased age and higher nocturnal stool frequency post-ileal pouch anal anastomosis. Only two studies met inclusion criteria for medication-related complications, one observed an increased mortality and infection risk among elderly patients treated with tumor necrosis factor antagonists and the other observed increased hospital-related complications among elderly patients treated with steroids. CONCLUSIONS: Elderly patients with IBD are at an increased risk of hospital- and therapy-related complications. We found a paucity of high-quality studies evaluating outcomes in elderly patients with IBD. Further studies of elderly patients with IBD are needed to further evaluate the effect of age on medical and surgical complications.

Dietary dilemmas, delusions, and decisions.

One of the most frequent questions gastroenterologists are asked about is diet, health, and disease; and some of the questions gastroenterologists are least comfortable answering are about diet, health, and disease. This disconnect occurs for several reasons. Although the subject of nutrition is taught in medical school, it usually covers malabsorption of nutrients, vitamins, and minerals that have limited relevance to the concerns of most patients. The modern physician does not see many cases of scurvy or beri beri. Physicians make decisions and recommendations from evidence-based medicine. Unfortunately, there is a dearth of sound data on diet and gastrointestinal diseases, forcing physicians to operate outside their comfort zone.

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.

Small bowel amyloidosis.

Amyloidosis often involves the gastrointestinal tract. The small intestine is the most commonly involved gastrointestinal site. Gastrointestinal manifestations of amyloidosis involvement of the small intestine include diarrhea, gastrointestinal bleeding, and obstruction. High index of suspicion leading to early diagnosis is important in tailoring appropriate therapeutic management of these patients.

Inflammatory bowel disease characteristics and treatment in Hispanics and Caucasians.

BACKGROUND: Many inflammatory bowel disease (IBD) studies have focused on Caucasian patients and little data exist on IBD in Hispanics living in the United States. AIM: The aim of our study was to compare IBD characteristics between Hispanic and Caucasian patients in the Harris County Hospital District (HCHD). METHODS: We identified patients within the HCHD with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) recorded during 2000-2006. Primary medical record review was performed to confirm the diagnosis and to abstract data on patient demographics, disease characteristics and treatment. RESULTS: A total of 69 Hispanic and 83 Caucasian patients with confirmed IBD were analyzed. Hispanics were diagnosed with IBD at an older age than Caucasians (mean age 37.8 SD 16 vs. mean age 29.0 SD 14, P < 0.01). In Hispanics with IBD, there was a lower proportion of patients with CD compared to Caucasians with IBD (36% vs. 65%, P < 0.01). Although there were no significant differences in diagnostic examinations or medication prescription between the two groups, there was a higher number of bowel resections per patient in Caucasians compared with Hispanics (0.5 vs. 0.22, P = 0.01). CONCLUSIONS: Hispanics with IBD were diagnosed at a significantly older age than Caucasians and had a lower number of bowel resections per patient. In Hispanics with IBD, UC was more common than CD while CD was more common than UC among Caucasians with IBD. Further research is required to confirm these observations and determine if these findings reflect genetic or environmental differences.

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.

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.

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.

Long-term follow up of patients with obscure gastrointestinal bleeding examined with video capsule endoscopy.

BACKGROUND: Video capsule endoscopy (VCE) is a commonly used test for the evaluation of obscure gastrointestinal bleeding. However, long-term outcomes of patients undergoing VCE are unclear. AIMS: To evaluate the long-term outcomes in patients undergoing VCE for suspected obscure bleeding including iron deficiency anemia (IDA), and determine the need for additional intervention for persistence or recurrence of symptoms in patients with a diagnostic as well as non-diagnostic VCE. DESIGN: Retrospective cohort study within a large county hospital system. METHODS: We collected information on indications and findings of VCE and outcomes including further testing, bleeding, and hemoglobin (Hgb) at last follow-up through structured review of the electronic health records. VCE findings were classified as active bleeding or high potential for bleeding (P2), intermediate potential (P1) or without any disruption of the mucosa, and no potential for bleeding (P0). We compared demographic and clinical characteristics between patients with and without normal Hgb at the time of last follow up. RESULTS: We examined 116 patients who underwent VCEs performed for obscure gastrointestinal (GI) bleeding during 2010 to 2012 with mean duration of follow up after VCE completion of 571 days (standard deviation [SD] = 248). Abnormal VCE findings (37.9% for P1 lesions, 44.8% for P2 lesions) were seen in 106 (87.9%) patients. Additional diagnostic testing was performed in 55/116 (47.4%) (67.7% GI procedures). Hgb was restored to normal range in 59/116 (50.9%) by end of follow up which were attributed to iron supplementation and/or discontinuation of non-steroidal anti-inflammatory drugs (NSAIDs) in a majority. Twenty six of 116 patients experienced rebleeding (22.4%). CONCLUSIONS: The diagnostic yield of VCE is high among patients with obscure GI bleeding. More than 50% of patients achieve normal Hgb in the long term with conservative measures such as iron supplementation and the discontinuation of NSAIDs.

A practical approach to treating patients with chronic diarrhea.

Although diarrhea is a common complaint, its evaluation and treatment can be challenging. Appropriately defining and classifying diarrhea provide the framework for approaching diagnostic and therapeutic options. Diarrhea can be defined based on frequency, consistency, and/or weight, and classified as acute or chronic with specific clinical characteristics and stool appearance. Colonoscopy is the most common diagnostic tool used in the evaluation of patients with chronic diarrhea. Other evaluation strategies include timed stool collections, evaluation of inflammatory markers, and hydrogen breath tests. A focused workup of chronic diarrhea may yield a specific diagnosis, including diarrhea-predominant IBS (dIBS), functional diarrhea, diabetic diarrhea, bile acid-induced diarrhea, and microscopic colitis. Ideally, therapeutic decisions are specifically tailored to target the underlying pathophysiology, including, for example, gluten restriction for celiac disease, rotating antibiotics for small bowel bacterial overgrowth, budesonide therapy for collagenous colitis, and loperamide for treatment of functional diarrhea. It is also important to assess the role of diet and medications in chronic diarrhea. However, if no specific causes are identified following workup, empiric therapy with simple opiate antidiarrheals such as loperamide may be effective. If this proves unsuccessful, the use of more potent agents, including codeine and opium, may be considered.

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.

Epithelial proliferation induces novel changes in APC expression.

The role of wild-type adenomatous polyposis coli (APC) protein in native epithelia is poorly understood. The present study examined the relationships between wild-type APC and beta-catenin expression in an established model of hyperproliferation, transmissible murine colonic hyperplasia (TMCH). Distal colonic crypts isolated from normal or TMCH mice were: (i) fractionated into cytosolic and nuclear components for Western blotting and immunoprecipitation (IP), (ii) extracted for total RNA isolation for Northern blotting and, (iii) analysed immunohistochemically by confocal microscopy. Western blots performed sequentially through day 12 TMCH with N-terminal APC antibodies revealed increased abundance of approximately 312 kDa (p312) protein by day 6 (4.0 +/- 0.75-fold, n = 6) that peaked by day 9, before declining by day 12. A approximately 130 kDa (p130) band appeared at day 9 and increased by day 12 (1.5 +/- 0.11-fold, n = 6). A C-terminal antibody detected only p312. APC mRNA level did not change during TMCH and appearance of p130 was not due to alternative splicing. Co-IP with N-terminal anti-APC antibodies, revealed APC's association with beta-catenin both at day 6 and day 12. p130, but not p312, associated predominantly with beta-catenin at day 12 during co-IP with anti-beta-catenin. p130 also selectively accumulated in the nucleus, bound to nuclear beta-catenin at day 12. Immunocytochemistry with N-terminal antibodies revealed an increasing crypt base : surface gradient of APC within the apical pole/apical-lateral membranes at day 6. At day 12, intense apical/cytoplasmic and occasional nuclear staining along the longitudinal crypt axis was observed. Full-length APC increases during epithelial hyperproliferation and may represent a homoeostatic response. The dramatic increase in cytoplasmic and sporadic nuclear APC staining at day 12 with N-terminal antibodies may represent p130. The nuclear accumulation of p130 may be a novel mechanism regulating nuclear beta-catenin function during TMCH.