PART 1
The 17th International Symposium on Gastrointestinal Motility was held in nice locations in Bruges, Belgium. In total 225 abstracts were accepted for the symposium. The major part of the symposium was focussed on receptor kinetics, action of hormones, and basic physiology in animal models. Organ hypersensitivity, evoked potentials, projections of gut innervation to the brain level, and interstitial cells of Cajal were other major issues. The number of studies related to daily clinical problems was relatively sparse, though functional diseases such as irritable bowel syndrome and non-cardiac chest pain were subject for a few studies. Studies based on intraluminal pressure recordings for extended time periods were almost lacking, and hence also papers dealing with the interdigestive migrating motor complex. Despite that several interesting studies and keynote lectures were presented, there seemed to be only little news under the sun. Perhaps this is caused by the short time between this symposium and the preceding symposium in Lorne, Australia.
Raj Goyal from Boston gave a keynote lecture on mechanisms and consequences of loss of nitrergic innervation in the GI tract. He presented data from the n-NOS knock-out mice model. He found that n-NOS deficiency did not induce gross changes in oesophageal morphology despite abnormalities in oesophageal function. Studies based on mutant animal models seems slow to gain widespread use in neurogastroenterology. Another study on mutant mice was presented by Gregersen and co-workers. They quantified the morphometric and biomechanical alterations in collagen-deficit oim mice compared to wildtypes.
Several papers were presented on interstitial cells of Cajal (ICC). Furthermore, Szurszewski and Sanders both gave very interesting invited lectures on the issue whether "there is more to rhythms than ICCs" or whether "there is more to ICCs than rhythm". Interstitial cells seems to play a role, not only for the production of basic smooth muscle rhythm, but also as intermediate and modulating units, both between motor neurons and smooth muscle cells, and for regulation of the flow of information from muscle to nerve. Thus, ICC’s seems interposed between both cholinergic nerves, NANC-fibres and smooth muscle cells (Huizinga, Hamilton, Canada). A function as stretch receptors was proposed. In the stomach, pacemaker activity as well as the spread of this activity depend on ICC’s (Szurszewski, Rochester).
André Smout (Utrecht) gave a critical lecture on the use of electrogastrography (EGG) for clinical diagnostic purposes. Normal rhythm and regular tachygastria might be diagnosed by this method. Irregular rhythms can not be assessed unless mucosal electrodes are applied, and he questioned the diagnostic entity of bradygastria.
Visceral hypersensitivity has been claimed important to the pathogenesis of various disorders, such as functional dyspepsia and non-cardiac chest pain. The cerebral projections of visceral sensation are being intensively studied and compared to the projections of comparable somatic stimulation. Studies have often been performed by means of balloon distension, for instance in the oesophagus, rectum, and now also in the antrum of the stomach (Ladabaum, Ann Arbor). Barlow, Thompson and Gregersen proposed in a joint study between Hope Hospital in Manchester and Aarhus University that the methodology of impedance planimetry can be used for better control of the applied stimulus and relate the responses to quantitative measurements of tension and deformation. They found that patients with non-cardiac chest pain had poorer tolerance to the distension procedure and provided evidence that the oesophagus in this group is less compliant.
At the last motility symposium a year ago, a drink test was suggested as a simple alternative to using a barostat for assessment of proximal gastric dysfunction. Boeckxstaens (Amsterdam) compared a water test with a caloric liquid test in normals and in patients with functional dyspepsia. He found that non-dysmotility-related dyspeptic patients can drink more water than caloric liquid, a difference that lacked in patients with dysmotility-related dyspepsia. This patient group had an impaired capacity for both water and caloric liquids. This simple test was, however, criticised by several members of the audience.
Tougas (Montréal) had studied gastric emptying in relation to age and gender with scintigraphic methods. He found the fat content to be the major determinant of emptying in older males, whereas the caloric content was a more important factor in older females and in young subjects.
The GABA receptor agonist Baclofen, that is able to reduce the number of transient lower oesophageal sphincter relaxations, was discussed on several occasions. Staunton (Adelaide) found a significant effect on transient relaxations, also for high gastric loads of liquid or liquid plus gas, in an animal model. In addition, Lehmann (Sweden) found a direct inhibition on swallowing after pharyngeal stimulation. The potentials of GABA receptor agonists for the treatment of gastro-oesophageal reflux disease remain to be determined, but more studies are to be expected.
In the section "New Drugs, New Therapies" James Christensen from Iowa gave an overview of the computer model he and Roustem Miftakhov developed. The model simulates the behaviour of a neuro-muscular unit in the intestine. The influence of drugs acting on the membrane level by means of changing ion currents and calcium dynamics can be simulated, aiding in the selection of relevant subsequent laboratory experiments. A two-dimensional computer simulation of the modeled stomach was provided by Indireshkumar and co-workers. The model was able to simulate that local time changes in gastric pressure and motions are directly correlated with antral contraction wave activity and that the efficiency of mixing is directly related to antral contraction wave characteristics. Without doubt computer simulations will be an important tool in neurogastroenterology research in the future, especially due to its powerful prediction capabilities of drug release and effects.
The Janssen Award was given to Fernando Azpiroz from Barcelona for his work on gastrointestinal perception. The lecture was entitled "Visceral sensitivity and gastrointestinal symptoms" and mainly dealt with the development of the barostat for gastric perception studies.
Several SAGIM members were present at the symposium. However, only about 3% of the presented abstracts came from or involved the Scandinavian countries. A more intense collaboration between Scandinavian laboratories might help to improve the statistics.
The next meeting will be chaired by Sushil Sarna and will be held in Wisconsin.
Hans Gregersen
Lab for Gastrointestinal Biomechanics, Motility Laboratory, Aalborg University, Denmark
Søren Kruse-Andersen
Center for Sensory-Motor Interaction Odense University Hospital, Odense, Denmark
PART 2
A total of 225 abstracts were presented at this International symposium with 6 from Scandinavia (3 from Sweden and 3 from Denmark). In the next milennium the name of this meeting will be changed to International symposium on neurogastroenterology and motility. The next symposium will be in Madison Wisconsin USA in the fall of year 2001.
The symposium started with the anniversary of one hundred years of the law of the intestine was presented by the enthusiastic G I Bowell !! from Darmstadt!! A video was shown for the participants demonstrating Dr. Bowell´s research on the peristalsis in the rabbit intestine performed with skill and elegance and his will to share his knowledge with fellow investigators in this field. His talk on peristalsis outside the gut was interesting and his conclusion was that peristalsis might also exist in the urinary tract although that needs further investigations.
Esophagus
At the last International symposium a motor event was described in the esophagus that correlates with non-cardiac chest pain. This unique motor pattern, sustained esophageal contraction (SEC) had now by the same group (Mittal et al. San Diego USA) been shown to be closely associated with heartburn symptoms. Reflux of acid in the esophagus can cause heartburn or chest pain. However, the mechanism of acid induced pain is not known and both of these symptoms can occur in the absence of acid reflux. Prolonged pH recordings show a poor correlation between the drop in pH in the esophagus and heartburn. SEC is recorded by high-frequency intraluminal ultrasound imaging of the esophagus. In 12 patients with heartburn, a close association between SEC and symptom of heartburn was observed. SEC may therefore be the motor event that causes heartburn sensation and could explain why later can occur in the absence of heartburn.
Despite the logical rationale whereby delayed gastric emptying and prolonged intragastric retention of food can increase the rate of transient LES (TLESRs) and reflux, only a moderate correlation has been previously described between proximal gastric retention and TLESRs in patients with gastroesophageal reflux disease (GERD). Investigators from Leuven (Sifrim et al. Belgium) tested the hypothesis that simultaneous measurement of reflux by both intraluminal impedance and ph monitoring as well as gastric emptying, would better characterize the relationship between gastric emptying, TLESRs and reflux. Esophageal manometry and ph was recorded 4 hours postprandially in healthy subjects and gastric emptying was measured by octanoic breath test. The impedance techinque was able to identify both acid and/or non-acid liquid or gas reflux. A significant correlation was found between gastric retention, the number of TLESRs and occurrence of predominantly liquid reflux (acid and non-acid). Impedance detected early postprandial acid and or non-acid liquid reflux whose frequency corrlelated weakly but significantly with the degree of gastric retention. In contrast, acid reflux detected by the pH monitoring did not correlate with gastric retention, perhaps due to buffering of acid in the early postprandial period.
Thus, new techniques such as intraluminal impedance and high-frequency intraluminal ultrasound imaging of the esophagus can better elucidate the normal physiology and
the pathophysiology of the esophagus and help us understand the underlying mechanisms in health and disease.
The role of hiatal hernia in patients with GERD has been a matter of debate. In patients with heartburn and acid regurgitation, hiatal hernia size correlated significantly with 24 h GER episodes (Lenglinger et al. Austria). Hiatal hernia size together with LES pressure, but not the amplitude of contractile responses to swallowing and oesophageal clearance time, are of major impact for the extent of gastroesophageal reflux.
Stomach
Antireflux surgery effectively controls acid reflux but about 30 % of patients develop dyspeptic symptoms such as fullness and early satiety. Bloating and upper abdominal discomfort can sometimes be invalidating for these patients and it is therefore of great importance to study the pathophysiology of these complications of this type of surgery. These symptoms may result from alterations in motor and sensory function of the proximal stomach. Gastric emptying and sensory thresholds as well as postprandial gastric relaxation was evaluated prospectively in patients who were undergoing hemifundoplication (Vu et al. Leiden Netherlands). Vagus nerve function, evaluated by PP response after insulin-induced hypoglycemia was intact in all patients. The lag phase for gastric emptying was significantly shorter after hemifundoplicatio but the overall rate of gastric emptying was not altered by the surgery. Proximal gastric compliance was not altered by the operation. However, postprandial gastric relaxation was significantly reduced compared to before surgery. The sensation of fullness in response to meal ingestion was significantly increased after hemifundoplication.
Ingestion of a meal induces relaxation of the proximal stomach and this relaxtion is more pronounced by increasing the fat content of the meal. It has been demonstrated previously that exogenous CCK induces gastric relaxation. Researchers from the same group (van der Schaar et al. Leiden, Netherlands) performed a study in order to further elucidate the role of endogenous and exogenous role of CCK on proximal motor and sensory function of the stomach. Healthy volunteers were given three kind of meals on different days. Fat rich meal (endogenous CCK) together with carbohydrates, carbohydrate rich meal without fat (accompanied by exogenous CCK infused i. v.) and carbohydrate rich meal without fat (accompanied by placebo i. v.). Intragastric relaxation was significantly increased after the fat rich meal together with carbohydrates compared with the carbohydrate rich meal lacking fat, although CCK was infused to identical plasma levels. Sensation of fullness was also more pronounced after the fat-rich meal compared with the other two meals. It was concluded that CCK only partially explains the effect of fat on the proximal gastric relaxation.
Recently, it was demonstrated that impaired accommodation of the proximal stomach to a meal is associated with early satiety and weight loss. A further elucidation of the motor mechanisms of the proximal stomach was presented by the same group (Tack et al. Leuven, Belgium). If impaired accommodation of the proximal stomach is the cause of early satiety, pharmacologically induced contraction of the gastric fundus might be beneficial for treating patients with obesity. The effects of motilin on the proximal stomach in man is unknown. Healthy volunteers participated in a barostat study measuring postprandial gastric volumes and a satiety test was performed with and without the administration of motilin. Adminstration of motilin caused a significant decrease of the intragastric balloon volume. Pretreatment with motilin significantly decreased the amount of food ingested at maximum satiety and significantly increased average satiety scores for the same amount of kcal ingested. It was hypothesized that the effect of motilin on satiety is mediated through a contraction of the gastric fundus.
Healthy aging is associated with a reduction in food intake which may predispose to severe anorexia. Possibly, this might be due to alterations in intragastric mechanisms mediating satiety. Sensory function and postprandial relaxation was compared between males between 68-73 years of age and young men, between 22-27 years (Rayner et al. adelaide, Australia). These healthy subjects participated in a barostat study in order to evaluate the effects of aging on the sensory and motor function of the proximal stomach. Compliance of the proximal stomach was not affected by aging. However, aging was associated with reduced perception of the gastric distention and a delay in maximum gastric relaxation, although maximal volume change after meal was similar in both age groups. Although, this study included only 5 subjects in each group, the effects of higher age can not be ignored in future studies on proximal gastric function.
Functional dyspepsia
Nausea and vomiting are gastrointestinal manifestations of migraine. The aim of this study in patients with dysmotility-like dyspepsia was to investigate the relationship between the headache and gastric emptying (Pallotta et al. Rom, Italy). Gastric emptying was measured in consecutive patients identified to have a headache that always preceded the dyspeptic symptoms. These patients had either common migraine or classical migraine. Gastric emptying was found to be delayed in the presence, and normal in absence of headache.
A caloric drink test was further tested in a group of dyspeptic patients by the same investigators in collaboration with italian colleagues (Cuomo et al. Leuven, Belgium and Napoli, Italy). Patients with moderate/severe early satiety ingested significantly less Kcal compared to patients without this symptom.
Dysfunction of the proximal stomach, assessed by a gastric barostat study, is increasingly recognized as underlying mechanism causing functional dyspeptic symptoms. Water-loading test has recently been proposed as an easy alternative tool for measuring proximal gastric function. At this meeting, Boeckxstaens et al. (Amsterdam, Netherlands) presented a comparison of a water and a caloric liquid drink test and evaluated if these tests could discriminate between patients with functional dyspepsia and controls. The dyspeptic patients were devided into dysmotility-like dyspeptics and non-dysmotility-like dyspeptics (NDLD). Both healthy volunteers and NDLD drank significantly more water than caloric liquid (Nutridrink). This difference was lacking in patients with dysmotility-like dyspepsia. These results suggest an increased sensitivity to distention and mechanoreceptor mediated response. The combination of these two drinking tests may represent a simple non-invasive tool to further investigate dysmotility-like dyspepsia.
The relationship between job stress and physiopathological mechanisms in functional dyspepsia was studied in consecutive patients still working. Results from a barostat study, measuring the sensitivity to distention and gastric accomodation as well as gastric emptying were correlated with results from a quality of work questionnaire. An association was found between job stress dimensions and the symptomatology and physiopathology of functional dyspepsia. For instance, job insecurity was significantly correlated with the total intensity of dyspepsia symptoms. Patients with gastric hypersensitivity had significantly lower levels of social support (of the boss!!), lower job satisfaction. Patients with a lack of meal-induced fundus relaxation had a higher levels of workload.
Diabetes mellitus and gastrointestinal symptoms
The true prevalence of GI symptoms in patients with diabetes mellitus (DM) is still not well appreciated. In a study from the United States (McCallum et al. Kansas City) frequency of different GI symptoms were studied in 125 consecutive patients with DM and a comparison was made between type I and type II DM. GI symptoms were present in 72% in type I and 77.5% in type II. Heartburn (44%) was the most common symptom in type II, followed by bloating (43%), nausea (29%), belching and constipation (27%). In type I, bloating (58%) was the most common symptom, followed by nausea (45%), belching and early satiety (39%) and heartburn (36%). In contrast to previously published studies, upper gastrointestinal symptoms are more common than lower GI symptoms. The prevalence of GI symptoms seems to be similar in both types of DM. Symptoms of gastroesophageal reflux seems to dominate the picture in type II DM in comparison with type I DM whose clinical picture was dominated by symptoms in the spectrum of gastic dysmotility and dyspepsia.
The predictive value of gastroparesis for symptoms and pathologies of the upper and lower GI tract was studied in diabetes mellitus (Greving et al. Bochum, Germany). Gastric emptying was measured by octanoic breath test. When patients were devided into those with and without GI symptoms, a similar proportion of symptomatic patients had gastroparesis or not (60% vs. 50%, respectively). Thus much documentations supports the view that diabetic gastroparesis is not predictive of GI symptoms and pathologies and GI symptoms do not predict a pathological test of gastric emptying.
Esophageal and gastric manometry had been peformed in patients with DM (Wittman et al. Szeged, Hungary). Although several and sometimes serious fasting states upper GI motility disorders could be found in long standing DM, only postprandial motility disorders showed correlation with the degree of the diabetic autonomic neuropathy.
Irritable bowel syndrome (IBS)
The pathophysiology of IBS receives more and more interest among researchers in the field of gastrointestinal motility. Thusfar, colonic motility studies in IBS have been performed for relatively short period of time in a laboratory setting, which might have limited the knowledge of colonic motility in IBS patients. Motor activity was recorded in non-constipated IBS patients during 24 hours (Clemens et al. Utrecht, Netherlands). The authors reported higher contraction frequency and motility index in the sigmoid colon compared to the descending colon. This regional difference was not seen in the healthy volunteers.The incidence and propagation velocity of high amplitude propagated contractions were increased in these non-constipated IBS patients.
Approximately 20-30% of IBS patients develop their symptoms originally after a gastroenteritis. This association with infectious gastroenteritis has tuned up the infectious hypothesis in the research of the etiopathogenesis of this bothersome syndrome. Spiller and coworkers at the Unversity of Nottingham have previously reported enteroendocrine (EC) hyperplasia which persists for at least 3 months following Campylobacter enteritis. These cells contain diarrhogenic amine, 5- hydroxytryptamine (5-HT). 42 patients had a rectal biopsy stained for synaptophysin by immunocytochemistry (Spiller at al.Nottingham, UK). EC were counted and the results compared with results from healthy controls. Enteroendocrine hyperplasia similar to that seen after Campylobacter enteritis was also seen in 22/42 patients with chronic diarrhea of unknown cause. The authors hypothesized that this might be a marker of post-infectious IBS.
Further characterization of camylobacter enteritis had been performed by the same group (Spiller at al.Nottingham, UK). A cohort of patients followed after a campylobacter enteritis were investigated with special consideration to GI peptides and enteroendocrine cells. Biopsies were stained immunocytochemically for synaptophysin, a docking protein associated with secretory granules and also for their peptide content with antibodies to 5-HT, PYY and somatostatin. EC hyperplasia following campylobacter enteritis is associated with an increase in 5-HT and PYY containing cells. Total EC cell numbers were not related to clinical outcome. However, EC hyperplasia might be a useful marker of previous infection in patients with functional diarrhea according to the authors.
Plasma levels of several GI peptides were measured after administration of lipids into the duodenum in healthy volunteers and patients with IBS (Simrén et al. Göteborg, Sweden). Levels of CCK, PP, PYY, VIP and NPY increased after duodenal lipids compared to after saline in both controls and IBS patients. However, levels of motilin were higher in the IBS group as a whole compared to healthy volunteers. Moreover, in diarrhea-predominant IBS motilin levels were higher than after saline but in constipation predominant IBS, the levels diminished significantly after lipids compared to saline. These differences can be of importance in the pathogenesis of IBS.
Visceral sensitivity was tested in IBS patients at differents levels in the gut (esophagus, duodenum, jejunum, ileum, colon and rectum) in constipation-predominant IBS (CPIBS) patients. Hypersensitivity could be identified in throughout the whole gut in both patients with urge and no-urge CPIBS. However, hyposensitivity was confined to the non-urge group, and as with hypersensitivity, can be observed in any region of the gut.
Slow transit constipation
In patients admitted to a gastroenterology clinic for the diagnostic work-up of chronic constipation, long-term small bowel manometry could frequently demonstrate disturbed small bowel function (Schmidt et al. München,Germany). Abnormal manometry findings overlap with slow transit constipation (STC) and constipation predominant IBS (IBS-C), and in both syndromes motor abnormalities point towards a neuropathy or a pseudobstruction in the small intestine. Postprandial hypomotility was significantly more frequent in in the STC group as weel as disturbed migration of phase III. Hower, excess of clustered contractions were more common in the IBS-C group.
Altered function in the proximal stomach was reported in patients with slow transit constipation (Penning et al. Leiden, Netherlands). Proximal compliance was not affected but postprandial gastric relaxation was impaired in the patients and symptom perception was significantly reduced.These findings point to alterations in proximal gastric motor and sensory function and perception and are in line with recent observations of autonomic neuropathy in slow transit constipation.
Pharmacological agents.
Sumatriptan, a 5-HT 1 receptor agonist with actions in the central nervous system as well as in the gut has been proposed as a therapeutic alternative in dyspeptics with early satiety. Sumatriptan was found in this study (Schäfer et al. Düsseldorf, Germany) to lower rectal compliance in healthy volunteers. Sumatriptan decreases perception of rectal distention, although distention volumes to induce specific sensations were unaffected. These effects of the drug are in part due to changes in rectal wall compliance but might also be attributed to central effects of the drug.
Octreotide is indicated in several gastrointestinal disorders. In a pilot study (open trial) a french group (Ducrotté et al. Rouen, France) studied the effects of Octreotid administered subcutaneously for the relief of chronic refractory epigastric pain severe enough to provoke nutritional impairment. 17 patients were enrolled, 8 following antireflux surgery and occurred spontaneously in the rest. The initial dose of Octreotide was 50 µg bid then adapted during the follow-up visits. In 15 of 17 patients a significant therapeutic improvement in pain intensity was reported. These reults have to be confirmed in a placebo-controlled study.
In mechanically ventilated patients critically ill patients 70 mg of erythromycin was as effective as 200 mg in the acceleration of gastric emptying (Ritz et al. Adelaide, Australia). Erythromycin was found to be most useful in patients with severely delayed gastric emptying.
Unfortunately, other interesting abstract are not reported on. It is impossible to discuss all important areas in this brief summary of this meeting. I have left out most of the very interesting animal model data and recent discoveries in pediatric gastroenterology and much more. Those who thirst for more GI motility knowledge can read all the abstract from this meeting in the latest number of he journal of Neurogastroenterology and motility.
Einar Björnsson, Asssociate Professor of Gastroenterology,
Sahlgrenska University Hospital, Göteborg, Sweden.