Canadian Association of Gastroenterology Clinical Practice Guidelines: The use of tumour necrosis factor-alpha antagonist therapy in Crohn's disease.

BACKGROUND: Guidelines regarding the use of infliximab in Crohn's disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines. OBJECTIVE: To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn's disease. METHODS: A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement). OUTCOME: The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication. CONCLUSION: In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn's disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn's disease is substantial and strengthened by results from longterm clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated.

Centre-specific multichannel electrogastrographic testing utilizing wavelet-based decomposition.

Although the principles of electrogastrography (EGG) have been known for years, the clinical utility of EGG has not been clearly demonstrated, and EGG recording and analysis techniques have not been fully standardized. The aim of this study was to develop a multichannel EGG technique for detecting abnormal gastric motility using an EGG database specifically designed for a particular testing centre, maximizing the sensitivity and the specificity of the test. Eight healthy volunteers formed a reference group to which 4 study groups (17 gastro-oesophageal reflux disease (GORD) patients, 7 functional dyspepsia patients, 8 post-fundoplication patients and 12 healthy volunteers) were compared. Eight-channel EGG was recorded in the postprandial and fasting states for 30 min each. The recorded signals were wavelet compressed and the resulting error (per cent root mean square difference (PRD)) after the compression was utilized to compare the study groups to the reference group. A threshold in the number of channels with significantly different PRD values was introduced. Sensitivity (SE), specificity (SP) and correct classification rate (CC) of the test in recognizing each clinical condition in the study groups for several channel thresholds and compressions were calculated, and were maximized. Increasing the compression and channel threshold levels improved the specificity, but decreased the sensitivity of the multichannel EGG test. An optimal combination region was identified based on a centre-specific adjustment of the channel threshold and the wavelet compression. The achieved maximum sensitivity, specificity and correct classification for this region in our test centre were as follows: GORD--SE 82.4%, SP 83.3%, CC 82.8%; functional dyspepsia--SE 100%, SP 75%, CC 84.2%; post-fundoplication--SE 75.0%, SP 83.3%, CC 80.0%. The utilization of a wavelet-based decomposition technique to process multichannel EGG signals can be a very effective method for enhancing the clinical utility of EGG, provided it is specifically developed for a given testing centre.

Proline transport across the intestinal microvillus membrane may be regulated by membrane physical properties.

There is now abundant evidence that integral membrane protein function may be modulated by the physical properties of membrane lipids. The intestinal brush border membrane represents a membrane system highly specialized for nutrient absorption and, thus, provides an opportunity to study the interaction between integral membrane transport proteins and their lipid environment. We have previously demonstrated that alterations in this environment may modulate the function of the sodium-dependent glucose transporter in terms of its affinity for glucose. In this communication we report that membrane lipid-protein interactions are distinctly different for the proline transport proteins. Maximal transport rates for L-proline by either the neutral brush border or imino transport systems are reduced 10-fold when the surrounding membrane environment is made more fluid over the physiological range that exists along the crypt-villus axis. Furthermore, in microvillus membrane vesicles prepared from enterocytes isolated from along the crypt-villus axis a similar gradient exists in the functional activity of these transport systems. This would imply that either the functional activity of these transporters are regulated by membrane physical properties or that the synthesis and insertion of these proteins is coordinated in concert with membrane physical properties as the enterocyte migrates up the crypt-villus axis.

Drug interactions with antacids. Mechanisms and clinical significance.

Concomitant use of antacid preparations with other medications is common. The potential for antacid-drug interactions is dependent upon the chemistry and physical properties of the antacid preparation. The intragastric release of free aluminum and magnesium ions has potent effects on gastrointestinal function and on drug pharmacokinetics. Antacid-drug interactions may occur secondary to changes in gastrointestinal motility or alterations in gastric and urinary pH. Direct adsorption also results in decreased drug bioavailability. Human drug interaction studies are usually performed with healthy volunteers; extrapolation of these results to clinical situations may not always be valid. However, the current literature would suggest that significant interactions with antacids do occur with certain members of the quinolone, nonsteroidal anti-inflammatory drug (NSAID) and cephalosporin classes of drugs. Notable interactions also occur with tetracycline, quinidine, ketoconazole and oral glucocorticoids. These interactions are particularly relevant in the patient with sepsis, cardiac disease or inflammatory syndromes.

Use of octreotide in the acute management of bleeding esophageal varices.

Acute hemorrhage from esophageal varices is a medical emergency; despite early diagnosis and treatment the associated hospital mortality remains high. The clinical research summarized in this paper shows that octreotide has a beneficial effect on portal hemodynamics in cirrhotic patients. In randomized controlled trials octreotide has been effective in halting initial hemorrhage and in preventing reoccurrence of bleeding. Somatostatin and octreotide appear to be equivalent in terms of therapeutic efficacy but octreotide is the less expensive option. For suspected variceal bleeding an octreotide infusion should be initiated immediately. To prevent further bleeding the drug should be continued for two to five days after endoscopic variceal ligation.

Cholestatic hepatocellular injury with azathioprine: a case report and review of the mechanisms of hepatotoxicity.

Azathioprine is a drug commonly used for the treatment of inflammatory bowel disease, organ transplantation and various autoimmune diseases. Hepatotoxicity is a rare, but important complication of this drug. The cases reported to date can be grouped into three syndromes: hypersensitivity; idiosyncratic cholestatic reaction; and presumed endothelial cell injury with resultant raised portal pressures, venoocclusive disease or peliosis hepatis. The components of azathioprine, 6-mercaptopurine and the imidazole group, may play different roles in the pathogenesis of hepatotoxicity. The strong association with male sex, and perhaps with human leukocyte antigen type, suggests a genetic predisposition of unknown type. Many of the symptoms of hepatotoxicity, such as nausea, abdominal pain and diarrhea, can be nonspecific and can be confused with a flare-up of inflammatory bowel disease. As well, the subtype resulting in portal hypertension can occur without biochemical abnormalities. A 63-year-old man with Crohn's disease who is presented developed the rare idiosyncratic form of azathioprine hepatotoxicity, but also had a severe disabling steroid myopathy, peripheral neuropathy, resultant deep venous thrombosis and pulmonary embolism related to immobility, and a nosocomial pneumonia. His jaundice and liver enzyme levels improved markedly on withdrawal of the drug, returning to almost normal in five weeks. Treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle. Understanding the risks of treatment is the first important step. There must be a low threshold for obtaining liver function tests, especially in men, and alertness to the need to discontinue the drug or perform a liver biopsy should patients on azathioprine develop liver biochemical abnormalities, unexplained hepatomegaly or signs of portal hypertension.

Prospective study of biliary strictures to determine the predictors of malignancy.

BACKGROUND: There have been few prospective studies regarding the investigation of biliary strictures, principally because of rapid technological change. The present study was designed to determine the sensitivity of various imaging studies for the detection of biliary strictures. Serum biochemistry and imaging studies were evaluated for their role in distinguishing benign from malignant strictures. METHODS: Thirty-one patients with suspected noncalculus biliary obstruction were enrolled consecutively in the study. A complete biochemical profile, ultrasound, Disida scan and cholangiogram (endoscopic retrograde cholangiopancreatography [ERCP] or percutaneous cholangiogram) were obtained at study entry. Stricture etiology was determined based on cytology, biopsy and/or clinical follow-up at one year. RESULTS: Twenty-nine of 31 patients had biliary strictures, of which 15 were malignant. The mean age of the malignant cohort was 73.9 years versus 53.9 years in the benign cohort (P<0.001). Statistically significant differences between the malignant and benign groups, respectively, were as follows: alanine transaminase 235.2 versus 66.9 U/L (P=0.004), aspartate transaminase 189.8 versus 84.5 U/L (P=0.011), alkaline phosphatase 840.2 versus 361.1 U/L (P=0.002), bilirubin 317.8 versus 22.1 micromol/L (P<0. 001) and bile acids 242.5 versus 73.2 micromol/L (P=0.001). Threshold analysis using receiver operative characteristic (ROC) curves demonstrated that a bilirubin level of 75 micromol/L was most predictive of malignant strictures. Intrahepatic duct dilation was present in 93% of malignant strictures versus 36% of benign strictures (P=0.002). Common hepatic duct dilation was less discriminatory (malignant 13.5 versus benign 9.6 mm; P=0.11). Ultrasound was highly sensitive (93%) in the detection of the primary tumour in the bile duct or pancreas, or in the visualization of nodal or liver metastases. In benign disease, ultrasound failed to detect evidence of intrahepatic or extrahepatic biliary dilation in most cases. Disida scans were not able to distinguish between malignant or benign strictures and could not accurately localize the level of obstruction. The sensitivity of Disida scan for the diagnosis of obstruction was 50%. Cholangiographic characterization of strictures revealed an equal distribution of smooth (eight of 13) and irregular (five of 13) strictures in the malignant group. Ten of 13 benign strictures were characterized as smooth. Malignant strictures were significantly longer than benign ones - 30.3 versus 9.2 mm (P=0.001). Threshold analysis using ROC curves showed that strictures greater than or equal to 14 mm were predictive of malignancy (sensitivity 78%, specificity 75%, log odds ratio 11.23). CONCLUSIONS: A serum bilirubin level of 75 micromol/L or higher, or a stricture length of greater than 14 mm was highly predictive of malignancy in patients with a biliary stricture. Ultrasound was useful in predicting malignant strictures by detecting either intrahepatic duct dilation or by visualizing the tumour (primary or metastases). Strictures with a 'benign' cholangiographic appearance are frequently malignant. Disida scan did not add additional information. ERCP is necessary to diagnose benign strictures, which tend to be less extensive at presentation.

Clinical parameters and symptom severity in males with fecal leakage and incontinence.

BACKGROUND: Despite the commonality of fecal incontinence (FI) in men, few studies have been carried out in this patient group. The aim of the study was to determine the contributions of clinical and physiological factors to symptom severity in males with fecal leakage (FL) and FI. METHODS: The records of all male patients referred for evaluation of FI and FL over a 6-year period were analyzed. For each male case, the records of three age-matched female controls with FI or FL were retrieved. All patients completed symptom assessment questionnaires (Vaizey score) and standard anorectal manometry testing. KEY RESULTS: A total of 100 males and 300 age-matched female controls were included. Vaizey scores were similar between sexes. For all Vaizey strata, males had normal maximal resting pressures (MRP) as well as normal maximal squeeze pressure (MSP). Females had a significantly reduced MRP and MSP across all Vaizey strata. In the FL subgroup, males had higher MRP and MSP than females. A multivariable linear regression analysis in males did not identify any clinical factors predictive of symptoms severity. For females, increased symptom duration, abnormal Bristol score, and reduced MSP were associated with worsening in Vaizey score. CONCLUSIONS & INFERENCES: For females, FL represents one end of the severity spectrum of FI while in males FL has a distinct pathophysiology. Contributing factors to symptoms in males with FL are not identified by routine clinical tests; however, anorectal manometry may identify a subgroup of FL males with low anal sphincter pressures that may respond to targeted interventions.

Intraluminal ultrasonic probe for volumetric monitoring of liquid gastroesophageal reflux.

Methods for volumetric monitoring of liquid gastroesophageal reflux (GER) are still lacking. The aim of this study was to develop an automated intraluminal measurement technique which allows ambulatory volumetric quantification of liquid GER utilizing a minimum-cost intraluminal ultrasonic probe. This probe consists of two 2 MHz ultrasonic crystals longitudinally assembled along a multi-channel intraluminal impedance (MII) catheter. The proposed probe was initially tested with tubular phantoms of different diameters. Measurements of the cross-sectional areas of the phantoms showed high correlation with the actual areas (R(2) = 0.99). Subsequently, two in-vivo human tests were performed. For each human test the catheter assembly was inserted transnasally and the ultrasonic probe was placed in the area of the lower esophageal sphincter. Multiple liquid swallows of different volumes were invoked using electrolyte drinks. Sectional luminal volume (SLV) in the esophagus between the two ultrasonic crystals was obtained. Results of the swallows demonstrated that measured SLVs correlated with the actual swallowed liquid volume. The ultrasonic probe was combined with a MII catheter to discriminate between antegrade and retrograde bolus transit. Increases of SLVs during liquid GER episodes could be utilized to evaluate GER volume in the vicinity of the ultrasonic probe.

Achalasia: incidence, prevalence and survival. A population-based study.

BACKGROUND: Studies of achalasia epidemiology are important as they often yield new insights into disease etiology. In this study, our objective was to carry out the first North American population-based study of achalasia epidemiology using a governmental administrative database. METHODS: All residents in the province of Alberta, Canada receive universal healthcare coverage as a benefit. The provincial health ministry, Alberta Health and Wellness, maintains a central stakeholder database of patient demographic information and physician billing claims. We defined an achalasia case as a billing claim submitted for the years 1996-2007 with an ICD-9-CM code of 530.0 or 530 and a Canadian Classification of Procedure treatment code of 54.92A (endoscopic balloon dilation) or 54.6 (esophagomyotomy). A preliminary validation study of the case definition demonstrated a sensitivity of 85% and specificity of 99% for known cases and controls. KEY RESULTS: A total of 463 achalasia cases were identified from 1995 to 2008 (59.6% males). Mean age at diagnosis was 53.1 years. In 2007, the achalasia incidence was 1.63/100,000 (95% CI 1.20, 2.06) and the prevalence was 10.82/100,000 (95% CI 9.70, 11.93). We observed a steady increase in the overall prevalence rate from 2.51/100,000 in 1996 to 10.82/100,000 in 2007. Survival of achalasia cases was significantly less than age-sex matched population controls (P < 0.0001). CONCLUSIONS & INFERENCES: Using a population-based approach, the incidence and prevalence of treated achalasia is 1.63/100,000 and 10.82/100,000, respectively. The disease appears to have a stable incidence but a rising prevalence. Survival of achalasia cases is significantly less than age-matched healthy controls.

Maintenance of clinical benefit in Crohn's disease patients after discontinuation of infliximab: long-term follow-up of a single centre cohort.

BACKGROUND: Tumour necrosis factor-blockade with infliximab has advanced the treatment of Crohn's disease. While infliximab is efficacious, it remains to be determined whether patients who enter clinical remission with an anti-tumour necrosis factor therapy can have their treatment stopped and retain the state of remission. AIM: To assess in patients with Crohn's disease who obtained infliximab-induced remission, the proportion who relapsed after infliximab discontinuation. METHODS: This longitudinal cohort study examined patients from a University-based IBD referral centre. Forty eight patients with Crohn's disease in full clinical remission and who then discontinued infliximab were followed up for up to 7 years. Crohn's disease relapse was defined as an intervention with Crohn's disease medication or surgery. RESULTS: Kaplan-Meier analysis of the proportion of patients with sustained clinical benefit demonstrated that 50% relapsed within 477 days after infliximab discontinuance. In contrast, 35% of patients remained well, and without clinical relapse, up to the end of the nearly 7-year follow-up. CONCLUSIONS: In patients with Crohn's disease with an infliximab-induced remission, stopping infliximab results in a predictable relapse in a majority of patients. Nevertheless, a small percentage of patients sustain a long-term remission.

Friction-assisted magnetic holding of an ingestible capsule for esophageal pH and impedance monitoring.

24-hour catheter-based ambulatory pH and impedance monitoring is an essential tool for diagnosing esophageal disorders. However, catheter-based monitoring systems are uncomfortable and interfere with normal activities of the patient. To overcome these disadvantages, different wireless monitoring systems have been proposed. However, efficient ways to position and hold wireless capsules are lacking. Currently there is a need to develop safe and reliable methods to hold an esophageal wireless monitoring system in position for 24 hours. Friction-assisted magnetic holding is proposed as an alternative to conventional holding techniques. Permanent magnet and electromagnet designs with the required characteristics to achieve this task were computer-designed and simulated. The size and power requirements of the magnets were considered. Simulation results were verified using laboratory experiments. Permanent neodymium magnets offered the best performance for the intended application. The obtained results show the feasibility of friction-assisted magnetic holding for esophageal monitoring. Improvements to the thread design, friction enhancing pins, magnetic shielding and encapsulation methods are necessary for in vivo testing.

Gastric ulcers at endoscopy: brush, biopsy, or both?

OBJECTIVES: All gastric ulcers discovered at endoscopy are potentially malignant. Concurrent use of both histological biopsy and cytological brushing has been advocated as a means of increasing the diagnostic yield for neoplasia at the time of initial endoscopy. The purpose of this analysis was to determine the impact of these diagnostic strategies on the cost-effectiveness of detecting malignancy in patients with a gastric ulcer. METHODS: The diagnostic performance of biopsy and brushings in detecting gastric malignancy was estimated from a meta-analysis of published reports. Nondiscounted direct costs were determined from patient resource consumer profiles from the perspective of a Canadian hospital. A decision tree was used to compare diagnostic strategies (biopsy alone, brushing alone, or biopsy and brushing) in a hypothetical cohort of patients found to have a gastric ulcer at endoscopy. Effectiveness was expressed as diagnostic days saved. RESULTS: No strategy achieved dominance. The brushing strategy was the most cost-effective, but its cost-effectiveness ratio was only slightly lower than that of biopsy. Cost differences between the biopsy and brushing strategies were small (less than $6 per case). Performing both biopsy and brushing slightly improved the true-positive rate but resulted in a doubling of the false-positive rate, which in turn led to unnecessary laparotomies. The impact of the high false-positive rate was also seen in the incremental cost of performing both brushings and biopsy ($168-$423 per case). CONCLUSIONS: For gastric ulcers discovered at endoscopy, the preferred strategy is to perform either cytological brushing or histological biopsy. The previously recommended strategy of performing both cytological brushing and histological biopsy should be reconsidered.

Luminal nutrients alter tight-junction permeability in the rat jejunum: an in vivo perfusion model.

The regulation of tight-junction permeability between enterocytes has been studied using in vitro perfused loops, Ussing chambers, and cultured cell monolayers. In this communication we demonstrate the ability of an in vivo perfusion model to monitor tight-junction permeability and respond appropriately to physiological luminal stimuli. By using the highly charged anionic ferrocyanide molecule, water flux could be accurately assessed in the rat, and the luminal clearance of high molecular weight dextrans could be used to probe the opening and closing of the paracellular pathway. By utilizing two different molecular weight dextrans markers simultaneously, each conjugated with a different fluorophore, we were able to calculate luminal clearances of these compounds by fluorometric techniques in the presence of luminal nutrients that have previously been demonstrated to open intercellular tight junctions. In the absence of luminal nutrients or the presence of a non-nutrient sugar such as mannitol, clearance of these compounds was negligible. However, with the addition of either D-glucose or L-alanine, clearance of both high molecular weight markers increased dramatically. Thus, opening of tight junctions between enterocytes appears to be a physiological event that occurs in vivo under conditions likely to be found in the lumen. Polyethylene glycol 400 (PEG-400) clearance did not correlate well with the clearance of either dextran marker, suggesting that this probe utilizes a different permeation pathway and may not be appropriate to quantify the nutrient-regulatable pathway observed with the former probes.

Biochemical models as early predictors of the etiology of acute pancreatitis.

In this study we observed the discriminative ability of five commonly measured laboratory tests to distinguish between gallstone- and non-gallstone-associated pancreatitis. We also assessed the ability of the lipase-amylase ratio to discriminate between alcohol- and non-alcohol-induced pancreatitis. One hundred sixty-two patients with acute pancreatitis were included in the study. Group A consisted of patients presenting to our hospital in 1988 and 1989. Group B consisted of patients presenting in 1992. Models developed using group A patients were validated using group B patients. For gallstone pancreatitis, AST (threshold value 80 IU/liter) alone and a three-factor model, AST, ALP and bilirubin (threshold values of 80 IU/liter, 115 IU/liter, and 15 mumol/liter, respectively) were the best predictors, correctly classifying at least 80% of cases in group A and B. A lipase-amylase ratio of two correctly classified only 48% of cases in group A and 54% in group B. We conclude that biochemical models are useful in predicting the presence of gallstone pancreatitis but not alcoholic pancreatitis.

Progressive type of focal nodular hyperplasia characterized by multiple tumors and recurrence.

Focal nodular hyperplasia (FNH) is usually a stable lesion that does not enlarge when studied for long periods of time; recurrence after resection has not been reported. We present a patient with a solitary FNH lesion that enlarged, was resected, and then recurred. A second resection was performed because of abdominal pain and disclosed multiple lesions, two of which were acutely infarcted. Thirty-two months later there was ultrasound evidence of further recurrence. Histology of the lesions showed the usual appearance of FNH with ducts and ductules in the central stalk regions but also some areas with minimal ductular differentiation and scanty connective tissue. Because of the clinical and histological appearance, the lesions in this patient were distinct from the usual type of FNH and merit the name "focal nodular hyperplasia, progressive type."