Justin Cy Wu

Psychological Co-morbidity in Functional Gastrointestinal Disorders: Epidemiology, Mechanisms and Management.

Functional gastrointestinal disorder (FGID) is one of the commonest digestive diseases worldwide and leads to significant morbidity and burden on healthcare resource. The putative bio-psycho-social pathophysiological model for FGID underscores the importance of psychological distress in the pathogenesis of FGID. Concomitant psychological disorders, notably anxiety and depressive disorders, are strongly associated with FGID and these psychological co-morbidities correlate with severity of FGID symptoms. Early life adversity such as sexual and physical abuse is more commonly reported in patients with FGID. There is mounting evidence showing that psychological disorders are commonly associated with abnormal central processing of visceral noxious stimuli. The possible causal link between psychological disorders and FGID involves functional abnormalities in various components of the brain-gut axis, which include hypothalamic-pituitary-adrenal system, sympathetic and parasympathetic nervous system, serotonergic and endocannabinoid systems. Moreover, recent studies have also shown that psychological distress may alter the systemic and gut immunity, which is increasingly recognized as a pathophysiologic feature of FGID. Psychotropic agent, in particular antidepressant, and psychological intervention such as cognitive behavioral therapy and meditation have been reported to be effective for alleviation of gastrointestinal symptoms and quality of life in FGID patients. Further studies are needed to evaluate the impact of early detection and management of co-morbid psychological disorders on the long-term clinical outcome and disease course of FGID.

Effects of intravenous and oral esomeprazole in the prevention of recurrent bleeding from peptic ulcers after endoscopic therapy.

OBJECTIVES:The use of intravenous proton-pump inhibitors (PPIs) has shown to reduce recurrent bleeding and improve patient outcome after endoscopic hemostasis on patients with peptic ulcer. However, the efficacy of oral PPI is uncertain. Studies from Asia indicated that even oral PPI can achieve the same therapeutic effect. This study is designed to compare the efficacy of high-dose intravenous PPI to oral PPI in preventing recurrent bleeding after endoscopic hemostasis.METHODS:This is a single-center, randomized-controlled, double-blind, and double-dummy study. Patients had Forrest IA/IB or IIA/IIB peptic ulcer bleeding and received endoscopic hemostasis before recruitment into the study. They were randomized to receive either (i) esomeprazole IV bolus at a dose of 80 mg plus infusion at 8 mg/h for 72 h and oral placebo every 12 h (IVP group), or (ii) IV placebo bolus plus infusion for 72 h and high-dose oral esomeprazole at a dose of 40 mg every 12 h (ORP group). Patients were followed up for 30 days after index bleeding. The primary end point was defined as the 30-day recurrent bleeding after successful endoscopic hemostasis.RESULTS:A total of 118 patients were randomized to the IVP group and 126 to the ORP group in this study. In all, 39.8% in the IVP and 42.9% in the ORP group used non-steroidal anti-inflammatory drug and/or aspirin before bleeding. In the IVP group (vs. ORP), Forrest IA represented 1.7% (5.6%), IB 41.5% (38.1%), IIA 52.5% (50.8%), and IIB 4.2% (5.6%). Recurrent bleeding in 30 days was reported in 7.7% of patients in the IVP group and 6.4% of patients in the ORP group, and the difference of recurrent bleeding was −1.3% (95% CI: −7.7%, 5.1%). There was no difference in blood transfusion, repeated endoscopic therapy, and hospital stay between the two groups.CONCLUSIONS:High-dose oral esomeprazole at 40 mg BID may be considered as a useful alternative to IV bolus plus infusion of esomeprazole in the management of ulcer bleeding in patients who are not candidates for high-dose IV infusion. However, as this study was stopped prematurely and was not designed as an equivalency trial, a much larger study would be necessary to document whether there is equivalency or non-inferiority of the two treatments in a heterogeneous patient population.

Effect of Electroacupuncture on Visceral Hyperalgesia, Serotonin and Fos Expression in an Animal Model of Irritable Bowel Syndrome

Background/Aims While it is well established that acupuncture relieves somatic pain, its therapeutic effect on visceral pain such as irritable bowel syndrome (IBS) is unclear. We evaluated the effect of acupuncture in treating visceral hyperalgesia in an animal model. Methods Sprague-Dawley rats (n = 8 per group) with prior neonatal maternal separation stress were randomly allocated to receive 3-day treatment of either electroacupuncture (EA) or sham acupuncture at acupoint ST-36. Another group of rats without prior maternal separation was included as non-handled controls. Colorectal distension was performed on the day after acupuncture treatment. The 3 groups were compared for pain threshold as determined by abdominal withdrawal reflex and visceromotor response as measured by electromyogram. Colon, spinal cord, and brainstem were sampled for topographic distribution and quantitative assessment of serotonin and Fos expression by immunohistochemistry. Results Rats in EA group had significantly higher pain threshold compared to those in sham acpuncture group (25.0 ± 5.7 mmHg vs 18.7 ± 5.2 mmHg, p = 0.01) and it was comparable with that of non-handled treatment naïve controls (29.4 ± 9.3 mmHg, p = 0.28). They also had lower visceromotor response as measured by electromyogram compared to those received sham acupuncture at all colorectal distension pressures. EA significantly suppressed Fos expression in doral raphe nuclei of brainstem, superficial dorsal horn of spinal cord and colonic epithelium but suppressed 5-HT expression only in brainstem and spinal cord. Conclusions Electro acupuncture attenuates visceral hyperlagesia through down-regulation of central serotonergic activities in the brain-gut axis.

Does Acupuncture Therapy Alter Activation of Neural Pathway for Pain Perception in Irritable Bowel Syndrome?: A Comparative Study of True and Sham Acupuncture Using Functional Magnetic Resonance Imaging

Background/Aims Patients with irritable bowel syndrome (IBS) are characterized by abnormal central processing with altered brain activation in response to visceral nociceptive signals. The effect of electroacupuncture (EA) on IBS patients is unclear. The study is set to study the effect of EA on brain activation during noxious rectal distension in IBS patients using a randomized sham-controlled model. Methods Thirty IBS-diarrhea patients were randomized to true electroacupuncture or sham acupuncture. Functional MRI was performed to evaluate cerebral activation at the following time points: (1) baseline when there was rectal distension only, (2) rectal distension during application of EA, (3) rectal distension after cessation of EA and (4) EA alone with no rectal distension. Group comparison was made under each condition using SPM5 program. Results Rectal distension induced significant activation of the anterior cingulated cortex, prefrontal cortex, thalamus, temporal regions and cerebellum at baseline. During and immediately after EA, increased cerebral activation from baseline was observed in the anterior cingulated cortex, bilateral prefrontal cortex, thalamus, temporal regions and right insula in both groups. However, true electroacupuncture led to significantly higher activation at right insula, as well as pulvinar and medial nucleus of the thalamus when compared to sham acupuncture. Conclusions We postulate that acupuncture might have the potential effect of pain modulation in IBS by 2 actions: (1) modulation of serotonin pathway at insula and (2) modulation of mood and affection in higher cortical center via ascending pathway at the pulvinar and medial nucleus of the thalamus.

Isorhynchophylline Treatment Improves the Amyloid-β-Induced Cognitive Impairment in Rats via Inhibition of Neuronal Apoptosis and Tau Protein Hyperphosphorylation

The progressive accumulation of amyloid-β (Aβ) in the form of senile plaques has been recognized as a key causative factor leading to the cognitive deficits seen in Alzheimers disease (AD). Recent evidence indicates that Aβ induces neurotoxicity in the primary neuronal cultures as well as in the brain. Previously, we have demonstrated that isorhynchophylline (IRN), the major chemical ingredient of Uncaria rhynchophylla, possessed potent neuroprotective effects. In the present study, we aimed to investigate the effect of IRN on cognitive function, neuronal apoptosis, and tau protein hyperphosphorylation in the hippocampus of the Aβ25-35-treated rats and to elucidate its action mechanisms. We showed that Aβ25-35 injection caused spatial memory impairment, neuronal apoptosis, and tau protein hyperphosphorylation. Treatment with IRN (20 or 40 mg/kg) for 21 days could significantly ameliorate the cognitive deficits induced by Aβ25-35 in the rats. In addition, IRN attenuated the Aβ25-35-induced neuronal apoptosis in hippocampus by down-regulating the protein and mRNA levels of the ratio of Bcl-2/Bax, cleaved caspase-3 and caspase-9, as well as suppressing the tau protein hyperphosphorylation at the Ser396, Ser404, and Thr205 sites. Mechanistic study showed that IRN could inhibit the glycogen synthase kinase 3β (GSK-3β) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3β activity and activation of PI3K/Akt signaling pathway are intimately involved in the neuroprotection of IRN. The experimental findings provide further evidence to affirm the potential of IRN as a worthy candidate for further development into a therapeutic agent for AD and other tau pathology-related neurodegenerative diseases.

Are meta-analyses of Chinese herbal medicine trials trustworthy and clinically applicable? A cross-sectional study

ETHNOPHARMACOLOGICAL RELEVANCE Meta-analysis (MA) on Chinese herbal medicine (CHM) trials is increasingly published and indexed in major international databases but their trustworthiness and clinical applicability is uncertain. We aimed to assess the characteristics and methodological quality of MA on CHM. MATERIALS AND METHODS Cross-sectional study. MA published during 1993-2013 was sampled from MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effect. Bibliographical characteristics were abstracted and methodological quality was assessed using the validated AMSTAR tool by two independent reviewers. RESULTS Total of 201 MA were included and half were published in or after 2009. Only 7.5% being updates of previous reviews. Majority are published in journals with low or no impact factor, with a median of 1.5. These MA demonstrated methodological strengths in ensuring comprehensive literature search, providing characteristics of the included studies, assessing the scientific quality of included studies and appropriately using the scientific quality of included studies in formulating conclusions. Nevertheless, weaknesses in protocol provision, listing of included and excluded studies, inclusion of grey literature, use of appropriate meta-analytic technique as well as reporting of funding sources were prevalent. CHM and control interventions pooled in majority of MA are found to have substantial clinical heterogeneity in terms of composition, dosage form and route of administration. CONCLUSIONS There are rooms for improvement in methodological rigor, and in choosing clinically homogenous interventions and control for statistical pooling. These shortcomings limit the trustworthiness and clinical applicability of existing MA on CHM trials. To overcome the limitations of pair-wise meta-analysis in synthesizing trials comparing different CHM and control interventions, the potential of network meta-analysis should be explored.

Chinese herbal medicine (Ma Zi Ren Wan) for functional constipation: study protocol for a prospective, double-blinded, double-dummy, randomized controlled trial

BackgroundFunctional constipation is a common clinical complaint. Although the effectiveness of Ma Zi Ren Wan for alleviating functional constipation symptoms has been proven in a previous randomized placebo-controlled study, further evidence is needed to make clinical recommendations about Chinese herbal medicine. In particular, a comparison with conventional western medicine for functional constipation patients is needed.Methods/DesignThis is a prospective, double-blinded, double dummy, randomized, controlled trial. After a 2-week run-in period, eligible patients (Rome III) with excessive traditional Chinese medicine syndrome will randomly be assigned to the Chinese medicine arm (Ma Zi Ren Wan and western medicine placebo), western medicine arm (senna and Chinese medicine placebo) or placebo arm (Chinese medicine placebo and western medicine placebo). Patients will undergo an 8-week treatment and an 8-week follow-up. The primary outcome is the responder rate for complete spontaneous bowel movement (CSBM) during treatment. Patients with a mean increase of CSBM ≧1/week in comparison with their baselines are defined as responders. The secondary outcomes include responder rate during follow-up, changes of colonic transit as measured with radio-opaque markers, individual and global symptom assessments, and reported adverse effects.DiscussionThis study is the first study to compare a Chinese Herbal Medicine (Ma Zi Ren Wan) with a laxative that is commonly used in the clinical practice of western medicine, and with a placebo. This study will complete the investigation of Ma Zi Ren Wan for functional constipation, and should, therefore, suggest recommendations for clinical practice. Furthermore, the process of first conducting a systematic review, then implementing a dose determination study followed by a placebo-control trial, and finally, comparing traditional Chinese medicine with an active conventional medicine in a controlled trial can be a reference to other researches on Chinese medicine interventions in the future.Trial registrationNCT01695850

Genetic polymorphism in pathogenesis of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a complex symptom-based disorder without established biomarkers or putative pathophysiology. IBS is a common functional gastrointestinal disorder which is defined as recurrent abdominal pain or discomfort that has at least two of the following symptoms for 3 d per month in the past 3 mo according to ROME III: relief by defecation, onset associated with a change in stool frequency or onset with change in appearance or form of stool. Recent discoveries revealed genetic polymorphisms in specific cytokines and neuropeptides may possibly influence the frequencies and severity of symptoms, as well as the therapeutic responses in treating IBS patients. This review gives new insights on how genetic determinations influence in clinical manifestations, treatment responses and potential biomarkers of IBS.

The role of capsule endoscopy in assessing mucosal inflammation in ulcerative colitis

Assessment of mucosal inflammation is important in the management of patients with ulcerative colitis (UC). Colon capsule endoscopy (CCE) has recently been shown to be effective in colorectal polyp detection. However, its role in the evaluation of mucosal inflammation in UC is unclear. This systematic review aims to clarify the state of the art with an evidence-based summary of current studies on the utility of CCE in UC. The overall results show that the accuracy of CCE for assessment of mucosal inflammation in UC appeared to be comparable with that of colonoscopy. Long-term follow-up studies with larger sample size are needed to further validate the utility of CCE in the management of UC subjects in clinical practice.

Endoscopic grading of reflux esophagitis in Asia: It's time to start

The diagnosis and grading of reflux esophagitis are important in the management of patients with gastroesophageal reflux disease (GERD). It enables the estimation of esophageal mucosal damage, the prediction of prognosis, and the monitoring of treatment response. An ideal endoscopic grading system of reflux esophagitis should have high sensitivity and specificity, which avoids the injudicious exclusion of patients at risk of disease progression, and the misdiagnosis of patients without GERD. It should also be simple and robust enough so that the interpretation can be relatively unaffected by the experience of endoscopist and endoscopic facilities. Furthermore, the classification should also be described in clearly defined and easily comprehensible terms so that precise communication among endoscopists is possible. There are over 30 different grading systems of reflux esophagitis. However, a formal development and validation process is lacking in most of these systems, and some have merely been published as secondary findings of clinical trials in patients with reflux esophagitis. There are no data on interobserver agreement, reproducibility, correlation with esophageal acid exposure, and the prediction of the treatment response rate in most of these systems. Other flaws include use of equivocal descriptions of endoscopic criteria, inclusion of minimal changes that are subjected to substantial interobserver variation, and incorporation of Barrett’s esophagus in the grading system. Because of these pitfalls, further revision on the original system is inevitable and several ‘modified’ versions are established, which create further confusion and hamper their application in clinical practice. To date, the Los Angeles (LA) classification is the only system that has been established through a stringent process of development, evaluation, and validation. It has some distinct features compared to other grading systems. First, minimal changes of non-erosive reflux disease (NERD), such as mucosal edema, friability, and erythema are not included, as these criteria have been shown to have very poor agreement. Second, the difficulty of differentiating between ‘red streak’, ‘ulcer’, and ‘erosion’ is obviated by adoption of a collective term known as ‘mucosal break’. In addition, the LA classification puts more emphasis on the circumferential extent of involvement instead of longitudinal extent, which has been found to be less precise and reproducible. The LA classification has been extensively employed in clinical trials for the medical treatment of reflux esophagitis. These studies further validate the LA classification as a powerful tool for predicting healing and relapse of esophagitis with acid-suppressive therapy. The superiority of the LA classification is further supported by significantly higher levels of interobserver agreement compared to the other two commonly-used systems. The LA classification has also been used in long-term observational and community-based epidemiological studies. While the LA classification has been proven to be a robust system for the assessment of esophagitis in Western countries, its validity has not been scrutinized in Asian countries. There are several factors that may undermine the validity of the LA classification in Asia. First, GERD is relatively less prevalent in Asia. Reflux symptoms are often overlooked and misinterpreted as dyspepsia or chest pain owing to low awareness by both clinicians and patients. Endoscopists may therefore have little vigilance on the likelihood of reflux esophagitis in these patients. Second, endoscopists in Asia may be less experienced in the assessment of esophagitis because of a lower prevalence of GERD complications. It has been reported that experience is a determinant of interobserver and intraobserver agreement for the endoscopic grading of esophagitis using the LA classification. In this issue of the Journal of Gastroenterology and Hepatology, Wong et al. set out to determine the interobserver agreement and validity of the LA classification in Asian GERD patients. Using video endoscopic clips of GERD patients, esophagitis and endoscopically-suspected Barrett’s esophagus were graded independently by three consultant endoscopists using the LA classification. An excellent interobserver agreement (kappa coefficient = 0.79) and good agreement (k = 0.48) were noted for the detection of esophagitis and endoscopically-suspected Barrett’s esophagus, respectively. Interobserver agreement was also good (k = 0.58) for the grading of esophagitis. There was also a learning effect observed with increasing agreement as viewings progressed. This study further supports the validity of the LA classification for the assessment of esophagitis in Asian countries, where prevalence, awareness, and case load of esophagitis are lower than their Western counterparts. The reported interobserver agreement of esophagitis grading in this study is comparable to that of Western studies. In this study, high image quality endoscopic video clips were used and the observers were allowed to pause and review selected segments at their individual preference. The viewing protocol can therefore come close to emulating live endoscopy. Another interesting finding of this study is the learning effect observed with the increasing number of video clips viewed and the improvement in interobserver agreement reached a plateau after 16 cases were viewed. The relatively small number of cases required to achieve this plateau suggests a steep learning curve with the use of the LA classification; this further supports that the LA classification is simple and easy to use. Despite promising results on interobserver agreement and the steep learning curve reported in this study, there are issues that remain unresolved. Further studies are required to test the robustness of the LA classification in less specialized setting. In clinical practice, the assessment of esophagitis is primarily conducted by endoscopists who have lower vigilance and less experience with probably limited accuracy in symptom description on endoscopy referrals. Furthermore, discriminative power between low-grade (A/B) and high-grade (C/D) esophagitis could not be properly Accepted for publication 16 September 2008.