Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid Diarrhea.

BACKGROUND AND AIMS: Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. METHODS: We performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator and outcome questions were developed through an iterative process and were voted on by a group of specialists. RESULTS: The certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea and Crohn's disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn's disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review and reinvestigation for patients whose symptoms persist despite BAST. CONCLUSIONS: Based on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with cholestyramine, is suggested.

Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid Diarrhea.

BACKGROUND & AIMS: Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. METHODS: We performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator, and outcome questions were developed through an iterative process and were voted on by a group of specialists. RESULTS: The certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy, or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea, and Crohn's disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn's disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review, and reinvestigation for patients whose symptoms persist despite BAST. CONCLUSIONS: Based on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with cholestyramine, is suggested.

Gallbladder cancer: epidemiology and outcome.

Gallbladder cancer, though generally considered rare, is the most common malignancy of the biliary tract, accounting for 80%-95% of biliary tract cancers. An early diagnosis is essential as this malignancy progresses silently with a late diagnosis, often proving fatal. Its carcinogenesis follows a progression through a metaplasia-dysplasia-carcinoma sequence. This comprehensive review focuses on and explores the risks, management, and outcomes for primary gallbladder carcinoma. Epidemiological studies have identified striking geographic and ethnic disparities - inordinately high occurrence in American Indians, elevated in Southeast Asia, yet quite low elsewhere in the Americas and the world. Age, female sex, congenital biliary tract anomalies, and a genetic predisposition represent important risk factors that are immutable. Environmental triggers play a critical role in eliciting cancer developing in the gallbladder, best exemplified by cholelithiasis and chronic inflammation from biliary tract and parasitic infections. Mortality rates closely follow incidence; those countries with the highest prevalence of gallstones experience the greatest mortality from gallbladder cancer. Vague symptoms often delay the diagnosis of gallbladder cancer, contributing to its overall progression and poor outcome. Surgery represents the only potential for cure. Some individuals are fortunate to be incidentally found to have gallbladder cancer at the time of cholecystectomy being performed for cholelithiasis. Such an early diagnosis is imperative as a late presentation connotes advanced staging, nodal involvement, and possible recurrence following attempted resection. Overall mean survival is a mere 6 months, while 5-year survival rate is only 5%. The dismal prognosis, in part, relates to the gallbladder lacking a serosal layer adjacent to the liver, enabling hepatic invasion and metastatic progression. Improved imaging modalities are helping to diagnose patients at an earlier stage. The last decade has witnessed improved outcomes as aggressive surgical management and preoperative adjuvant therapy has helped prolong survival in patients with gallbladder cancer. In the future, the development of potential diagnostic markers for disease will yield screening opportunities for those at risk either with ethnic susceptibility or known anatomic anomalies of the biliary tract. Meanwhile, clarification of the value of prophylactic cholecystectomy should provide an opportunity for secondary prevention. Primary prevention will arrive once the predictive biomarkers and environmental risk factors are more clearly identified.

Solitary lesions with fibrosis and increased IgG4+ plasma cells: part of the expanding spectrum of IgG4-related disease or a nonspecific inflammatory response?

We assessed 6 cases acquired during routine surgical sign-out for IgG4-related disease (IRD) according to criteria from a recent consensus meeting. These cases fulfilled the morphologic criteria-that is, dense lymphoplasmacytic infiltrates, IgG4:IgG ratio greater than or equal to 0.4, and fibrosis (storiform in 4 cases-but were associated with malignancy or did not fulfill the criteria for a new site. These criteria include increased serum IgG4 (normal in the majority of IRD) and a response to glucocorticoids, which is not appropriate treatment for resectable lesions as in our cases. Until more is known about the natural history of the disease, we propose that the possibility of an early, localized, or forme fruste of IRD should be considered and that cases associated with malignancy should at least be documented. Although we acknowledge the value of the consensus criteria, their strict application may result in missed opportunities to study the disease.

The association between celiac disease and eosinophilic esophagitis in children and adults.

BACKGROUND: An association between eosinophilic esophagitis (EoE) and celiac disease (CD) has been suggested in the literature. Our aim was to confirm and quantify the association between these two diseases. METHODS: All patients in a large Canadian city diagnosed with EoE or CD over a five-year period were identified. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated. RESULTS: Over the five-year study EoE was diagnosed in 421 patients and CD was diagnosed in 763 patients. The incidence of EoE ranged from 2.1 to 10.7 cases per 100,000 population. The incidence of CD ranged from 10.4 to 15.7 cases per 100,000 population. Among the EoE cohort, 83 (20%) cases of EoE and 245 (32%) cases of CD were diagnosed in pediatric patients. The incidence of EoE in the pediatric subpopulation ranged from 3.7 to 6.9 cases per 100,000 population. The incidence of CD in the pediatric subpopulation ranged from 9.5 to 22.7 cases per 100,000 population. The concomitant diagnosis of both EoE and CD was made in three patients, all of whom were pediatric males. The SIR for EoE in the CD cohort was 48.4 (95% CI = 9.73, 141.41) with a SIR for CD within the paediatric EoE cohort of 75.05 (95% CI = 15.08, 219.28). CONCLUSIONS: This study confirms the association between EoE and CD. However, this association may be limited to pediatrics where the risk of each condition is increased 50 to 75-fold in patients diagnosed with the alternative condition. The concomitant diagnosis of these conditions should be considered in pediatric patients with upper gastrointestinal symptoms.

Epidemiology of gallbladder disease: cholelithiasis and cancer.

Diseases of the gallbladder are common and costly. The best epidemiological screening method to accurately determine point prevalence of gallstone disease is ultrasonography. Many risk factors for cholesterol gallstone formation are not modifiable such as ethnic background, increasing age, female gender and family history or genetics. Conversely, the modifiable risks for cholesterol gallstones are obesity, rapid weight loss and a sedentary lifestyle. The rising epidemic of obesity and the metabolic syndrome predicts an escalation of cholesterol gallstone frequency. Risk factors for biliary sludge include pregnancy, drugs like ceftiaxone, octreotide and thiazide diuretics, and total parenteral nutrition or fasting. Diseases like cirrhosis, chronic hemolysis and ileal Crohn's disease are risk factors for black pigment stones. Gallstone disease in childhood, once considered rare, has become increasingly recognized with similar risk factors as those in adults, particularly obesity. Gallbladder cancer is uncommon in developed countries. In the U.S., it accounts for only ~ 5,000 cases per year. Elsewhere, high incidence rates occur in North and South American Indians. Other than ethnicity and female gender, additional risk factors for gallbladder cancer include cholelithiasis, advancing age, chronic inflammatory conditions affecting the gallbladder, congenital biliary abnormalities, and diagnostic confusion over gallbladder polyps.

Eosinophilic colitis: an update on pathophysiology and treatment.

BACKGROUND: Primary eosinophilic gastrointestinal disorders, a spectrum of inflammatory conditions, occurs when eosinophils selectively infiltrate the gut in the absence of known causes for such tissue eosinophilia. These may be classified into eosinophilic esophagitis, eosinophilic gastroenteritis and eosinophilic colitis (EC). This review focuses on EC: its pathogenesis, epidemiology, clinical presentation, diagnosis and current approach to treatment. SOURCES OF DATA: A literature review published in English was performed using Pubmed, Ovid, Google scholar search engines with the following keywords: eosinophilic gastrointestinal disorder, EC, eosinophils, colitis and gastrointestinal. AREAS OF AGREEMENT: The basis for primary EC appears related to increased sensitivity to allergens, principally as a food allergy in infants and a T lymphocyte-mediated event in adults. Endoscopic changes are generally modest, featuring edema and patchy granularity. AREAS OF CONTROVERSY: Clear clinical and pathological diagnostic criteria of EC and its management strategy. GROWING POINTS: Intestinal involvement of EC is primarily mucosal, presenting as a mild self-limited proctitis in infants and self-limited colitis in young adults. Therapeutic approaches based on case reports tend to use either elimination diets to avoid a presumed allergen; agents traditionally used in inflammatory disease or targeted drugs like anti-histamines or leukotriene receptor antagonists. AREAS TIMELY FOR DEVELOPING RESEARCH: Prospective randomized controlled trials addressing the disease natural history, possible preventive methods and effective medical approach and long-term prognosis are required.

Eosinophilic colitis: epidemiology, clinical features, and current management.

Primary eosinophilic gastrointestinal disorders (EGIDs) represent a spectrum of inflammatory gastrointestinal disorders in which eosinophils infiltrate the gut in the absence of known causes for such tissue eosinophilia. EGIDs can be subgrouped as eosinophilic esophagitis (EE), eosinophilic gastroenteritis (EG), and eosinophilic colitis (EC). The least frequent manifestation of EGIDs is EC. EC is a heterogeneous entity with a bimodal age distribution, presenting with either an acute self-limited bloody diarrhea in otherwise healthy infants or as a more chronic relapsing colitis in young adults. The pathophysiology of primary EC appears related to altered hypersensitivity, principally as a food allergy in infants and T lymphocyte-mediated (i.e. non-IgE associated) in young adults. In adults, symptoms include diarrhea, abdominal pain, and weight loss. Endoscopic changes are generally modest, featuring edema and patchy granularity. Although standardized criteria are not yet established, the diagnosis of EC depends on histopathology that identifies an excess of eosinophils. Therapeutic approaches are based on case reports and small case series, as prospective randomized controlled trials are lacking. Eosinophilic colitis in infants is a rather benign, frequently food-related entity and dietary elimination of the aggressor often resolves the disorder within days. Adolescent or older patients require more aggressive medical management including: glucocorticoids, anti-histamines, leukotriene receptors antagonists as well as novel approaches employing biologics that target interleukin-5 (IL-5) and IgE. This review article summarizes the current knowledge of EC, its epidemiology, clinical manifestations, diagnosis, and treatment.

Pneumatosis Coli Associated with Pseudomembranous Colitis in a Patient following Colonic Surgery.

Pneumatosis intestinalis is a rare disorder characterized by gas-filled cysts within the subserosal and/or submucosal regions of the intestinal wall. The source of this gas and its translocation across the mucosa is incompletely understood. Most (85%) cases are associated with medical conditions, ranging from psychiatric through respiratory disorders to gastrointestinal-related diseases; the remaining 15% lack any recognizable cause or association. In this case report, pneumatosis coli (affecting the colon) occurred in a patient following abdominal surgery and was associated with pseudomembranous colitis, which was Clostridium difficile toxin negative-presumably a false negative. Supportive care and appropriate antibacterial agents sufficed to alleviate symptoms and resolve the pneumatosis. Recognizing this uncommon but important association can avoid high financial and personal costs from unnecessary testing and invasive surgical explorations. Consideration should be given to pseudomembranous colitis as the basis for pneumatosis coli developing in patients who have received antibiotics, once gut ischemia has been ruled out.

Epidemiology of gallstones.

Gallstones are common with prevalences as high as 60% to 70% in American Indians and 10% to 15% in white adults of developed countries. Ethnic differences abound with a reduced frequency in black Americans and those from East Asia, while being rare in sub-Saharan Africa. Certain risk factors for gallstones are immutable: female gender, increasing age, and ethnicity/family (genetic traits). Others are modifiable: obesity, the metabolic syndrome, rapid weight loss, certain diseases (cirrhosis and Crohn disease), gallbladder stasis (from spinal cord injury or drugs, such as somatostatin), and lifestyle.

Gastroenterology fellowship training: approaches to curriculum assessment and evaluation.

BACKGROUND: Medical education requires ongoing curriculum development and evaluation to incorporate new knowledge and competencies. The Kern model of curricular development is a generic model to guide curriculum design, whereas the Royal College of Physicians and Surgeons of Canada (RCPSC) has a specific model for curriculum development through its accreditation structure. OBJECTIVE: To apply the Kern model to an assessment of a residency program in gastroenterology. METHODS: A case study was used, which is a method of qualitative research designed to help researchers understand people and the societal contexts in which they live. RESULTS: The six steps involved in the Kern model of curricular development include problem identification; needs assessment; establishing objectives; establishing educational strategies; implementation; and evaluation. The steps of the RCPSC model of curriculum development include establishing an administrative structure for the program; objectives; structure and organization of the program; resources; clinical, academic and scholarly content of the program; and evaluation. Two differences between the models for curriculum development include the ability of the Kern model to conduct problem identification and learner needs assessment. Identifying problems that exist suggests a need for an educational program, such as the long wait times for gastroenterology referrals. Assessing learner needs allows for the development of a tailored curriculum for the trainee. CONCLUSIONS: The Kern model and RCPSC model for curriculum development are complementary. Consideration by the RCPSC should be provided to add the missing elements of curriculum design to the accreditation structure for completeness.

Gallstone disease: current therapeutic practice.

Most asymptomatic gallstone carriers require no therapy. Laparoscopic cholecystectomy is the best definitive therapy for symptomatic gallstone disease. Selective laparoscopic cholecystectomy can provide secondary prevention of symptoms and complications in certain instances (in a complex clinical setting such as sickle cell disease or to prevent gallbladder carcinoma from developing in those at risk with large gallstones or with a calcified gallbladder). Primary prevention is unproven but focuses on early identification and risk alteration to decrease the possibility of developing gallstones. Ursodeoxycholic acid has a limited role for stone dissolution but can prevent stone development in severe obesity during rapid weight reduction with diet or after bariatric surgery. Endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy represents the therapeutic cornerstone for managing severe pancreatitis and cholangitis.

HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis.

UNLABELLED: Previous studies examining the relationship between HFE mutations and severity of nonalcoholic steatohepatitis (NASH) have been limited by small sample size or ascertainment bias. The aim of this study was to examine the relationship between HFE mutations and histological severity in a large North American multicenter cohort with NASH. Data from 126 NASH patients were collected from 6 North American centers. Liver biopsy and genotyping for the C282Y and H63D HFE mutations were performed in all subjects. Serum transferrin-iron saturation and ferritin levels as well as hepatic iron content were recorded whenever available. Univariate and multivariate logistic regression analyses were performed to identify factors associated with advanced hepatic fibrosis. The prevalence of heterozygous C282Y and H63D HFE mutations was 14.3% and 21.4%, respectively, in the overall cohort. Among Caucasians, C282Y heterozygotes were more likely to have bridging fibrosis or cirrhosis (44% versus 21% [P = 0.05]) and stainable hepatic iron (50% versus 16% [P = 0.011]) compared with patients with other genotypes. Diabetes mellitus was the only independent predictor of advanced hepatic fibrosis (OR 4.37, 95% CI 1.41-13.54 [P = 0.010]) using multiple logistic regression analysis adjusting for age, sex, ethnicity, body mass index, and HFE genotype status. CONCLUSION: The HFE C282Y heterozygous mutation is associated with advanced fibrosis among Caucasians with NASH. Additional studies are warranted to examine the possible mechanisms for this relationship.

Role for protease activity in visceral pain in irritable bowel syndrome.

Mediators involved in the generation of symptoms in patients with irritable bowel syndrome (IBS) are poorly understood. Here we show that colonic biopsy samples from IBS patients release increased levels of proteolytic activity (arginine cleavage) compared to asymptomatic controls. This was dependent on the activation of NF-kappaB. In addition, increased proteolytic activity was measured in vivo, in colonic washes from IBS compared with control patients. Trypsin and tryptase expression and release were increased in colonic biopsies from IBS patients compared with control subjects. Biopsies from IBS patients (but not controls) released mediators that sensitized murine sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor and was absent in neurons lacking functional protease-activated receptor-2 (PAR2). Supernatants from colonic biopsies of IBS patients, but not controls, also caused somatic and visceral hyperalgesia and allodynia in mice, when administered into the colon. These pronociceptive effects were inhibited by serine protease inhibitors and a PAR2 antagonist and were absent in PAR2-deficient mice. Our study establishes that proteases are released in IBS and that they can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR2.

Gallstone disease: Epidemiology of gallbladder stone disease.

Gallstone disease is common: >700,000 cholecystectomies and costs of approximately 6.5 billion dollars annually in the U.S. The burden of disease is epidemic in American Indians (60-70%); a corresponding decrease occurs in Hispanics of mixed Indian origin. Ten to fifteen per cent of white adults in developed countries harbour gallstones. Frequency is further reduced in Black Americans, East Asia and sub-Saharan Africa. In developed countries, cholesterol gallstones predominate; 15% are black pigment. East Asians develop brown pigment stones in bile ducts, associated with biliary infection or parasites, or in intrahepatic ducts (hepatolithiasis). Certain risk factors for gallstones are immutable: female gender, increasing age and ethnicity/family (genetic traits). Others are modifiable: obesity, the metabolic syndrome, rapid weight loss, certain diseases (cirrhosis, Crohn's disease) and gallbladder stasis (from spinal cord injury or drugs like somatostatin). The only established dietary risk is a high caloric intake. Protective factors include diets containing fibre, vegetable protein, nuts, calcium, vitamin C, coffee and alcohol, plus physical activity.

Effects of tegaserod on bile composition and hepatic secretion in Richardson ground squirrels on an enriched cholesterol diet.

BACKGROUND: Tegaserod is effective in treating IBS patients with constipation, and does not alter gallbladder motility in healthy individuals or in patients with IBS. However, it is not known if tegaserod affects the biliary tract in gallstone disease, so to this end the effects of tegaserod on bile composition and hepatic secretion of Richardson ground squirrels maintained on an enriched cholesterol diet were examined. RESULTS: Animals were fed either a control (0.03%) or enriched (1%) cholesterol diet for 28 days, and treated s.c. with tegaserod (0.1 mg/kg BID) or vehicle. Bile flow, bile acid, phospholipids and cholesterol secretion were measured with standard methods. Tegaserod treatment or enriched cholesterol diet, alone or combination, did not alter body or liver weights. The enriched cholesterol diet increased cholesterol saturation index (CSI), cholesterol concentrations in gallbladder and hepatic duct bile by approximately 50% and decreased bile acids in gallbladder bile by 17%. Tegaserod treatment reversed these cholesterol-induced changes. None of the treatments, drug or diet, altered fasting gallbladder volume, bile flow and bile salts or phospholipid secretion in normal diet and cholesterol-fed animals. However, tegaserod treatment prevented the decreases in bile acid pool size and cycling frequency caused by the enriched cholesterol diet, consequent to re-establishing normal bile acid to concentrations in the gall bladder. Tegaserod had no effect on these parameters with normal diet animals. CONCLUSION: Tegaserod treatment results in increased enterohepatic cycling and lowers cholesterol saturation in the bile of cholesterol-fed animals. These effects would decrease conditions favorable to cholesterol gallstone formation.

Eosinophilic esophagitis: a newly established cause of dysphagia.

Eosinophilic esophagitis has rapidly become a recognized entity causing dysphagia in young adults. This review summarizes the current knowledge of eosinophilic esophagitis including the epidemiology, clinical presentation, diagnostic criteria, pathophysiology, treatment, and prognosis. An extensive search of PubMed/Medline (1966-December 2005) for available English literature in humans for eosinophilic esophagitis was completed. Appropriate articles listed in the bibliographies were also attained. The estimated incidence is 43/10(5) in children and 2.5/10(5) in adults. Clinically, patients have a long history of intermittent solid food dysphagia or food impaction. Some have a history of atopy. Subtle endoscopic features may be easily overlooked, including a "feline" or corrugated esophagus with fine rings, a diffusely narrowed esophagus that may have proximal strictures, the presence of linear furrows, adherent white plaques, or a friable (crepe paper) mucosa, prone to tearing with minimal contact. Although no pathologic consensus has been established, a histologic diagnosis is critical. The accepted criteria are a dense eosinophilic infiltrate (>20/high power field) within the superficial esophageal mucosa. In contrast, the esophagitis associated with acid reflux disease can also possess eosinophils but they are fewer in number. Once the diagnosis is established, treatment options may include specific food avoidance, topical corticosteroids, systemic corticosteroids, leukotriene inhibitors, or biologic treatment. The long-term prognosis of EE is uncertain; however available data suggests a benign, albeit inconvenient, course. With increasing recognition, this entity is taking its place as an established cause of solid food dysphagia.