Are Downhill Varices an Overlooked Entity of Upper Gastrointestinal Bleedings?

AIM: Downhill varices are not so safe as thought and can lead to life-threating or mortal bleeding complication, even if rare. In order to draw attention to this topic, we analysed 129 patients. MATERIALS AND METHODS: We evaluated the electronic endoscopy data records of all patients undergoing upper gastrointestinal endoscopy over a nine-year period from January 2004 till December 2012, within a retrospective approach. The primary endpoints, incidence, causes, kind of resulting upper gastrointestinal bleeding, and the severity of the bleeding were evaluated. Secondary endpoints were the evaluation of the size of downhill varices and a comparison of the risk of bleeding between downhill varices and uphill varices. RESULTS: Downhill varices were identified, described, and/or documented in 129 patients of 25,680 upper gastrointestinal endoscopies. 26 patients had central venous catheter or port implantation, 22 patients had a history of an implantation of a cardiac pacemaker, 7 patients had severe pulmonary artery embolism, and 4 patients had severe chronic obstructive pulmonary disease. Two patients had mediastinal tumors, and one patient had a large retrosternal goiter as a possible cause of the vena cava syndrome. Altogether, 62 patients were related to a vena cava superior syndrome; 67 were not. CONCLUSIONS: Downhill varices can be seen with an incidence of 0.5%. Therapeutic means are the banding therapy as a safe and effective option. Severe bleedings associated with downhill varices can be mortal. Severe forms of downhill varices should be examined in relation to the origin in order to start a specific therapy.

Efficacy and safety of cold snare resection in preventive screening colonoscopy.

BACKGROUND AND AIM: Removal of polyps during colonoscopy effectively prevents the development of colorectal cancer. So far, snare resection with high frequency current with or without prior submucosal saline injection is the method of choice. The aim of this study was to evaluate the feasibility, safety, and outcome of cold snare resection during routine endoscopy. METHODS: In this prospective study, 522 patients undergoing outpatient colonoscopy were included. Cold snare resection for diminutive (< 6 mm), small (6 - 9 mm), and larger polyps (> 9 - 15 mm) was performed using a dedicated cold snare device (Exacto ® ) without prior submucosal injection. Outcome parameters included bleeding rate, perforation rate, procedure time, histologic evaluation of polyp margins, and success rates. The data were compared to a group of patients undergoing hot snare resection. RESULTS: Overall, 1233 polyps were removed using cold snare resection with an overall success rate of 99.4 %. All failures of cold snare resection occurred in the cecum (8/82, failure rate 9.8 %). In the remaining colon, the success rate was 100 %. Immediate post-polypectomy bleeding occurred in 0.49 % of all patients and was most frequently seen in polyps larger than 9 mm. The procedure time was significantly shorter using cold snare resection compared with hot snare resection (27.6 min vs. 35.7 min, P  < 0.01). CONCLUSION: Cold snare resection can be performed safely in outpatients for removal of small polyps in screening colonoscopy. It does not require prior saline injection and reduces procedure time without an increased risk of bleeding.

The selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056) reduces the incidence of reflux episodes in dogs and patients with moderate to severe gastroesophageal reflux disease.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) induced by gastric distension are modulated by the metabotropic glutamate receptor 5 (mGluR5) that influences the vagal reflex loop. We therefore aimed to examine the effects of the selective mGluR5 antagonist mavoglurant (AFQ056) on the number of TLESRs in dogs and reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: In a dog model, the number of meal-induced TLESRs was determined after intravenous (0.03, 0.1, 0.3, and 1 mg kg-1 ) and oral (1, 3, and 10 mg kg-1 ) doses of mavoglurant with reference to vehicle. In a multicenter, randomized, double-blind, placebo-controlled, three-period crossover study, the incidence of meal-induced reflux episodes was assessed by esophageal impedance monitoring after single, oral doses of mavoglurant (50 and 400 mg) or baclofen (40 mg) in 30 patients with moderate to severe GERD. KEY RESULTS: In dogs, mavoglurant reduced the number of TLESRs after intravenous and oral administration. In patients with GERD, the incidence of postprandial reflux episodes was significantly lower at a dose of 400 mg mavoglurant (-37.5% ; 90% confidence interval [CI]: -57.8, -17.2), whereas there was no significant difference at 50 mg of mavoglurant compared to placebo. A significantly lower incidence of reflux episodes was also noted with the active comparator baclofen (-50.3%; 90% CI: -66.2, -34.3), thereby validating this study. CONCLUSIONS AND INFERENCES: These data suggest a potential clinical benefit of mGluR5 antagonists such as mavoglurant in patients with GERD, particularly in those with persisting symptoms despite treatment with proton pump inhibitors.

[Sphincter of Oddi dyskinesia]. / Sphinkter-Oddi-Dyskinesie.

Sphincter of Oddi dyskinesia is a functional disorder of the papillary region which can lead to clinical symptoms due to functional obstruction of biliary and pancreatic outflow. Based on the severity of the clinical symptoms the disorder can be graded into three types (biliary and pancreatic types I-III). The manometric diagnosis of this disorder using sphincter of Oddi manometry is hampered by the relatively high risk of pancreatitis after endoscopic retrograde cholangiopancreatography. Although papillary manometry is often carried out in North America, in Europe this is the exception rather than the rule. Manometrically, sphincter of Oddi dyskinesia is characterized by an increased pressure in the biliary and/or the pancreatic sphincter segments and can be treated by endoscopic papillotomy. This overview counterbalances the arguments for primary invasive diagnostics and a pragmatic clinical approach, i.e. papillotomy should be directly carried out when a sphincter of Oddi dyskinesia is clinically suspected. For patients with biliary or pancreatic type I, endoscopic papillotomy is the treatment of choice. In biliary type II sphincter of Oddi manometry could be helpful for clinical decision-making; however, the exact risk-benefit ratio is still difficult to assess. In type III patient selection and the low predictive value of manometry for treatment success questions the clinical usefulness of sphincter of Oddi manometry.

[Chest pain - not always the heart! Clinical impact of gastrointestinal diseases in non-cardiac chest pain]. / Brustschmerz - nicht immer das Herz! Klinische Bedeutung gastrointestinaler Erkrankungen beim nicht-kardialen Thoraxschmerz.

Non cardiac chest pain (NCCP) are recurrent angina pectoris like pain without evidence of coronary heart disease in conventional diagnostic evaluation. The prevalence of NCCP is up to 70 % and may be detected in this order at all levels of the medical health care system (general practitioner, emergency department, chest pain unit, coronary care). Reduction of quality of life in NCCP is comparable, partially even higher compared to cardiac chest pain. Reasons for psychological strain are symptom recurrence in app. 50 %, nonspecific diagnosis with resulting uncertainty and insufficient integration of other medical disciplines in diagnostic work-up. Managing of patients with NCCP has to be interdisciplinary because non cardiac causes of chest pain may be found frequently. Especially gastroenterological expertise is required because in 50 - 60 % of cases gastroesophageal reflux disease (GERD), in 15 - 18 % hypercontractile esophageal motility disorders with nutcracker, jackhammer esophagus or distal esophageal spasmus or achalasia and in 32 - 35 % other esophageal alterations (e. g. infectious esophageal inflammation, drug-induced ulcer, rings, webs, eosinophilic esophagitis) as cause of chest pain may be detected. This implicates that regular interdisciplinary round wards and management of chest pain units are mandatory.

[Diagnosis of oesophageal reflux by PH, impedance, and bilirubin measurement: recommendations of the German Society of Neurogastroenterology and of the working group for neurogastroenterology of the German Society for Digestive and Metabolic Diseases]. / Ösophageale Refluxdiagnostik - pH-Metrie, Impedanzmessung, Bilirubin-Messung: Empfehlungen der Deutschen Gesellschaft für Neurogastroenterologie und Motilität und der Arbeitsgruppe Neurogastroenterologie der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten.

The current recommendations on indications, technical performance, and interpretation of diagnostic techniques for oesophageal reflux update the German recommandations about 24 hour pH measurement of 2003. The recommendations encompass conventional pH measurement, wireless pH measurement, pH and impedance measurements, and bilirubin measurement (duodenogastro-oesophageal reflux).

Effect of GABA-ergic mechanisms on synaptosomal NO synthesis and the nitrergic component of NANC relaxation in rat ileum.

BACKGROUND: γ-Aminobutyric acid (GABA) acts on specific neural receptors [A, B and C(Aρ)] to modulate gastrointestinal function. The precise role of GABA receptor activation in the regulation of presynaptic nitric oxide (NO) synthesis in nerve terminals is unknown. METHODS: Rat ileal nerve terminals were isolated by differential centrifugation. Nitric oxide synthesis was analysed using a L-[(3) H]arginine assay. In vitro studies were performed under non-adrenergic non-cholinergic (NANC) conditions on isolated ileal segments. KEY RESULTS: γ-Aminobutyric acid inhibited NO synthesis significantly (n = 6, P < 0.05) [(fmol mg(-1) min(-1)) control: 27.7 ± 1.5, 10(-6) mol L(-1): 19.7 ± 1.3; 10(-5) mol L(-1): 17.5 ± 3.0]. This effect was antagonized by the GABA A receptor antagonist bicuculline and the GABA C receptor antagonist (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), but not by the GABA B receptor antagonist SCH 50911. The GABA A receptor agonist muscimol [(fmol mg(-1) min(-1)) control: 27.6 ± 1.0, 10(-6) mol L(-1): 19.1 ± 1.7, n = 5, P < 0.05] and the GABA C receptor agonist cis-4-aminocrotonic acid (CACA) [(fmol mg(-1) min(-1)) control: 29.5 ± 3.2, 10(-3) mol L(-1): 20.3 ± 2.5, n = 6, P < 0.05], mimicked the GABA-effect, whereas the GABA B agonist baclofen was ineffective. Bicuculline reversed the inhibitory effect of muscimol, TPMPA antagonized the effect of CACA. In functional experiments the GABA A and C receptor agonists reduced the NANC relaxation induced by electrical field stimulation in rat ileum by about 40%. After NOS-inhibition by Nε-nitro-L-arginine methyl ester (L-NAME) the GABA A receptor agonist had no effect, whereas the GABA C receptor agonist still showed a residual response. CONCLUSIONS & INFERENCES: γ-Aminobutyric acid inhibits neural NO synthesis in rat ileum by GABA A and GABA C(Aρ) receptor-mediated mechanisms.

Functional dyspepsia: still a serious challenge for medical practitioners and new drug investigators? A Belgian, French, German and Hungarian opinion.

The diagnosis of Functional Dyspepsia is based on the identification of long term specific symptoms and the absence of organic lesions. Many pathophysiological mechanisms are intricate and, at least, partially responsible for the syndrome. Widely accepted technical procedures for the identification of these mechanisms are missing. The final etiopathology is not yet established. The relationship between symptoms and putative mechanisms is unclear. At the moment of the prescription, the physician faces a real therapeutic gap. Moreover, Functional Dyspepsia is an evolving area of study and knowledge has to be updated regularly. As a result, consultations for Functional Dyspepsia are usually very challenging and patients look desperately for medical support. It is likely that this disease is both under-diagnosed and under-treated. Classifying patients into symptomatic subgroups is a promising approach proposed by Rome III. It is assumed that these subgroups are based on different pathophysiological mechanisms, and may allow for more specific therapeutic approaches. However the assessment of the symptomatic profiles of patients is time-consuming. It is also a risky process, because the Rome III subgroups have yet to be validated. There are currently no translations of the definitions in the different European languages. Interviews of the patients are biased by cultural, educational and subjective factors. Identification of suitable subjects for clinical trials is uneasy for the same reasons and can explain several recent Research and Development (R&D) failures. Therefore, there is a need for an updated, step by step approach, a real diagnostic algorithm of the consultation including the use of simple, clear, universal and cross-cultural validated tools, as word-figure questionnaires, designed to establish the symptomatic profiles of the patients.

[Non-cardiac chest pain]. / Nicht-kardialer Thoraxschmerz.

Thoracic pain and discomfort are symptoms that lead many patients to the presentation in private practice or emergency admissions in hospitals. It is one of the most common complaints in the acute care setting. Attendant symptoms like agitation and fear are often signals of unstableness, but can also be alarming symptoms of an acute emergency. At first it is the main purpose to exclude an acute life-threatening event, such as acute coronary heart syndrome or pulmonary embolism. If a cardiac cause is excluded, the spectrum ranges from reflux disease and other oesophageal disorders to functional and vertebral thoracic pain. These other causes need an interdisciplinary assessment. The aim of this article is to summarize the differential diagnoses of non cardiac chest pain. The causes of non cardiac chest pain encompass a vast spectrum of various diseases with different needs of diagnosis and therapy.

Differential stimulatory effects of cannabinoids on VIP release and NO synthase activity in synaptosomal fractions from rat ileum.

Cannabinoid-1 (CB1) and CB2 receptors are present on neurons of the enteric nervous system. Our aim was to study whether cannabinoid receptor activation is involved in the regulation of VIP release and NO synthesis in isolated fractions of nerve terminals from rat ileum. VIP was measured by RIA and NO synthesis was analyzed using a L-[3H]arginine assay. Anandamide stimulated VIP release (basal: 245.9+/-12.4pg/mg, 10(-6)M: 307.6+/-11.7pg/mg, [n=6, P<0.05], 10(-7)M: 367.0+/-26.1pg/mg, [n=6, P<0.01]). The cannabinoid receptor agonist WIN 55,212-2 had similar effects (basal: 250.5+/-37.4pg/mg, 10(-6)M: 320.9+/-34.7pg/mg; [n=4, P<0.05]). The stimulatory effect of anandamide was blocked by the selective CB2 receptor antagonist, SR144528 (10(-7)M) (anandamide 10(-6)M: 307.6+/-11.7pg/mg; +SR144528: 249.0+/-26.3pg/mg, [n=6, P<0.05]), whereas the selective CB1 receptor antagonist SR141716 A had no effect. NO synthesis was stimulated by anandamide ([fmol/mg/min] basal: 0.08+/-0.01, 10(-6)M: 0.16+/-0.03; 10(-7)M: 0.13+/-0.02, n=4, P<0.05) and WIN 55,212-2 ([fmol/mg/min] basal: 0.05+/-0.01, 10(-6)M: 0.1+/-0.02, n=4, P<0.05). The anandamide reuptake inhibitor, AM 404 increased basal NOS activity ([fmol/mg/min] control: 0.1+/-0.04, 10(-6)M: 0.28+/-0.08, n=7, P<0.05). The stimulatory effect of anandamide on NO synthase was not antagonized by antagonists at the CB1, CB2 or TRPV1 receptor, respectively. In conclusion, in enteric nerves anandamide stimulates VIP release by activation of a CB2 receptor specific pathway, while the stimulation of NO production suggests the existence of an additional type of cannabinoid receptor in the enteric nervous system.

Do we need gastric acid?

Evidence from comparative anatomy and physiology studies indicates that gastric acid secretion developed during the evolution of vertebrates approximately 350 million years ago. The cellular mechanisms that produce gastric acid have been conserved over the millennia and therefore proton pump inhibitors have pharmacological effects in almost all relevant species. These observations suggest that gastric acid provides an important selective advantage; however, in modern-day humans the need for gastric acid can be questioned in light of the widespread use of safe and effective pharmacologic acid suppression. The Kandahar Working Group addressed questions concerning the need, production and effects of gastric acid, specifically: (1) motility in the upper gastrointestinal (GI) tract; (2) neuroendocrine factors; (3) digestive and mucosal processes; (4) microbiology, and (5) central processes and psychological involvement. We addressed each topic with the individual models available to answer our questions including animal versus human studies, pharmacologic, surgical as well as pathophysiologic states of acid suppression.

[Differential diagnosis of pancreatic lesions using endoscopic ultrasound]. / Endosonografische Differenzialdiagnose von Pankreastumoren.

The most common pancreatic tumour is the ductal adenocarcinoma. Many other benign and malignant pancreatic neoplasms have to be recognised and now account for more than 50 % of the pancreatic lesions seen in our daily routine. An improved differential diagnosis is, therefore, mandatory and will be discussed in this review.

Cannabinoid type 1 receptor modulates intestinal propulsion by an attenuation of intestinal motor responses within the myenteric part of the peristaltic reflex.

Cannabinoid-1 (CB1) receptor activation affects gastrointestinal propulsion in vivo. It was our aim to further characterize the involved myenteric mechanisms in vivo and in vitro. In CB1(-/-) mice and wild-type littermates we performed in vivo transit experiments by charcoal feeding and in vitro electrophysiological recordings in mouse small intestinal smooth muscle. Ascending neuronal contraction (ANC) following electrical field stimulation was studied in rat ileum in a partitioned organ bath separating the aboral stimulation site from the oral recording site. The knockout animals displayed an accelerated upper gastrointestinal transit compared to control animals. The CB1 receptor antagonist AM251 stimulated the force of the ANC in a concentration dependent manner when added in the oral chamber. Anandamide significantly inhibited the ANC when added in the oral chamber. Neither AM251 nor anandamide had an influence on the contraction latency. No effects were observed when drugs were added in the aboral chamber, proving a CB1 mediated action on the neuromuscular junction. Resting membrane potentials and neuronal induced inhibitory junction potentials in CB1(-/-) mice were unchanged as compared to wild type. However, the electrophysiological slow waves were more sensitive to blockade of Ca(2+) channels in CB1(-/-) mice. Our data strongly suggest a physiological involvement of the CB-1 receptor in the regulation of small intestinal motility. Therefore, CB1 receptors are a promising target for the treatment of motility disorders.

[Achalasia--early diagnosis and treatment options]. / Achalasie.

Achalasia is a rare motility disorder of the distal esophagus, showing reduced or absent swallow induced relaxation of the lower esophageal sphincter region. The onset of the disease can be very slow and correct diagnosis might be delayed over years. Using exact medical history, upper GI endoscopy and barium swallow X-ray the achalasia can be suspected and can be confirmed by esophageal manometry. Other especially malignant diseases, which can imitate the clinical symptoms, have to be ruled out. Pneumatic balloon dilatation is therapy of first choice in achalasia. Especially in younger patients laparoscopic fundoplication with subsequent antireflux procedure should be offered early in the therapeutic algorithm when dilatation therapy fails. Medical therapy or intrasphincteric injection of botulinum toxin is only an alternative treatment for high risk patients, treatment failures or residual symptoms.

Functional dyspepsia--a multicausal disease and its therapy.

Functional dyspepsia is a common chronic disorder with non-specific upper abdominal symptoms which can not be explained by organic or biochemical abnormalities. The dyspeptic symptoms are very compromising and bothersome and result in a substantial reduction of quality of life. The substantial direct and indirect medical and economical costs induce a high socioeconomic interest in the pathogenesis and the treatment options of this disease. Over the past 30 years several theories about the etiology of the symptoms in functional dyspepsia patients have been put forward. These include disorders of gastrointestinal motility, acid secretion, visceral hypersensitivity, adaptation and accommodation, Hp-infection, mucosal inflammation and finally genetic predisposition. There is increasing evidence that functional dyspepsia is a multi-causal disorder, which leads to altered processing of afferent information from the gastrointestinal tract to the CNS. Autonomic hypersensitivity and altered central processing could be a common phenomenon whereas motility changes, inflammation or altered secretion could increase neural afferent inputs. Treatment of this complex disorder could and should involve these different levels of symptom generation. Thus different approaches with anti-secretory, spasmolytic, prokinetic and anti-inflammatory effects and most preferably reduction of visceral hypersensitivity seem logical. This could explain the variety of drugs which show a positive symptomatic response. This could also offer the conclusion, whether a combination of these drugs could be clinically superior which remains to be proven. And this could offer a logical approach for the use of substances with a multi-target action, e.g. STW 5.

STW 5 (Iberogast) and its individual herbal components modulate intestinal electrophysiology of mice.

STW 5 (Iberogast), a phytomedicine agent consisting of a fixed combination of nine individual plant extracts, is widely used in the treatment of dyspepsia and motility related disorders. Little if anything is known on the possible influence on electrophysiological properties of intestinal smooth muscle by which STW 5 causes its beneficial effects. The aim of the present study was to investigate whether herbal extracts influence electrophysiological parameters of large and small intestine. For this purpose intracellular recordings of smooth muscle cell (SMC) of the circular muscle layer of different parts of mouse intestine were performed using standard microelectrode techniques. The resting membrane potential (RMP), excitatory and inhibitory neurotransmission in proximal colon, the frequency and the amplitude of slow waves in small intestine were investigated. The RMP of SMC was -46.4+/-3.8 mV, n=11 in the colon and -59+/-1.3 mV, n=15 in small intestine. STW 5 significantly depolarized the RMP of colonic (16.6+/-2.2 mV, n=6, p<0.05) and jejunal (9.6+/-1.6 mV, n=7, p<0.05) SMC. This depolarizing effect can be mainly attributed to the constituents of chamomile flower, Angelica root and greater celandine herb. Following the electrical field stimulations (EFSs), junction potentials are influenced in a distinct manner. Excitatory junctions potentials (EJPs) of the colon were not significantly reduced (13.1+/-4.8 vs. 10.1+/-2.8 n.s., n=6) but fast (fIJP) and slow (sIJP) inhibitory junction potentials of the murine colon are reduced significantly by STW 5 (fIJP: 21.6+/-8.1 vs. 11.6+/-2.1 and sIJP: 12.1+/-3.3 vs. 6.1+/-1.3 n=6, p<0.05). The basal frequency of small intestinal slow waves was 39.5+/-1.4 min(-1) and the amplitude was 23.1+/-0.9 mV, n=15. STW 5 significantly reduced amplitude and frequency of the slow waves (11.7+/-0.8 mV; 33.5+/-3.4 min(-1), n=6, p<0.05). This effect on slow waves represents the summation of effects of the nine individual phytoextracts. Whereas Angelica root and chamomile flower completely blocked the slow wave activity, bitter candy tuft increased the frequency and amplitude, greater celandine herb reduced frequency and amplitude of the slow wave, peppermint leaf reduced frequency and left amplitude unchanged and liquorice root, caraway fruit and lemon balm leaf had no effects in basic electrophysiological properties of SMC. This study demonstrates that STW 5 causes changes in SMC RMP, excitatory and inhibitory neurotransmission and slow wave rhythmicity. These effects represent a summation effect of different constituents of this phytotherapeuticum and prove that STW 5 has characteristic effects on intestinal electrophysiology.

CB1 and TRPV1 receptors mediate protective effects on colonic electrophysiological properties in mice.

CB1 and TRPV1 receptors modulate enteric neurotransmission and colonic inflammation. This study investigates early electrophysiological changes in distal colon of wild-type and receptor deficient mice after an inflammatory insult set by dinitrobenzene sulfonic acid (DNBS). Colitis was induced by DNBS in CB1(-/-) mice, TRPV1(-/-) mice, and their respective wild-type littermates. Electrophysiological properties consisting of membrane potentials and electrically induced inhibitory junction potentials (IJP) of circular smooth muscle cells were evaluated at different time points. Additionally a histological colitis severity score was evaluated in CB1(+/+) and CB1(-/-) mice 24 h after DNBS. Inflammation caused spontaneous atropine insensitive rhythmic action potentials in CB1(-/-) and TRPV1(-/-) mice but not in wild-type animals. This indicates that membrane stability is disturbed, which in turn indicates a lack of protective mechanisms. Focal electrical neuronal stimulation of the myenteric plexus induced IJP in the smooth muscle cells. Twenty-four hours after initiation of inflammation, the duration of the IJP is prolonged in all animals, indicating disturbances within neuromuscular interaction. In CB1(-/-) mice, it is interesting that the duration of IJP was significantly extended, as compared to CB1(+/+) mice pointing toward missing protective mechanisms in the CB1(-/-) mice. Inflammatory insults in the mouse colon induce reproducible changes in the electrophysiological properties and such changes correlate with duration of colitis. In mutants, these electrophysiological changes display different patterns, suggesting the lack of protective properties for neuromuscular interactions and membrane stability.