The association of gastroesophageal reflux with bronchial asthma. Can asthma also trigger reflux?

BACKGROUND/AIMS: The frequency of gastroesophageal reflux (GER) among asthmatic patients was found to range from 34% to 89% at different locations. The aims of this study have been to determine the frequency of GER in patients with asthma in the Saudi environment, to ascertain the main mechanism whereby GER triggers asthma, and to seek any evidence whether asthma can also trigger GER. METHODOLOGY: Fifty asthmatic patients were consecutively recruited as they reported to King Fahd Hospital of the University (KFHU), Al-Khobar, Saudi Arabia, in the period from February 2000 to February 2001; their mean age +/- SD was 38.0 +/- 9.8 years. Twenty-two subjects without asthma or GER served as controls; their mean age +/- SD was 29.4 +/- 8.6. Both groups were subjected to a questionnaire, esophageal manometry, dual probe ambulatory 24-hour pH monitoring, and pulmonary function tests. RESULTS: Among the asthmatic group 22 patients (44%) had GER. Accordingly, the asthmatic patients were divided into two groups: asthmatic with GER (n=22), and asthmatic without GER (n=28). Hoarseness of voice and nocturnal symptoms were found to be significant predictors for the presence of GER in asthmatics. Manometry revealed that asthmatic patients with GER had higher gastric pressure (11.4 +/- 4.0 mmHg vs. 8.4 +/- 2.8 mmHg; p=0.006) and lower resting pressure at the lower esophageal sphincter (LES) (21.2 +/- 8.7 mmHg vs. 28.2 +/- 9.3 mmHg; p=0.013) when compared with controls, both factors favoring the occurrence of reflux. With regard to pH data, acid reflux occurred both at the distal and proximal esophagus but the percent total acid exposure time was about 7 times longer at the distal than at the proximal esophagus (5.80 vs. 0.9). In addition, gastric pressure was positively and significantly correlated with distal esophageal acid exposure time and the DeMeester score, negatively correlated with spirometric parameters in asthmatic patients, as well as found to be a significant predictor of the severity of asthma (p=0.006). CONCLUSIONS: Forty-four percent of the sample of asthmatic patients reporting to KFHU had GER. Since distal esophageal total acid exposure time was nearly 7 times longer than at the proximal esophagus, the main mechanism for GER triggering asthma is the vagally mediated reflex initiated by acid in the distal esophagus. In addition, the positive correlation of increased gastric pressure with the distal esophageal acid exposure time and the DeMeester score, its negative correlation with spirometric parameters and being a significant predictor of asthma severity suggest that severe asthma may trigger or aggravate GER.

The brain of the gut.

One year before the close of the 19th century it was recognized that intestinal peristalsis was controlled by nerve plexuses in the wall of the gut independent of the central nervous system (CNS). This concept was developed further during the first quarter of the 20th century but was almost forgotten during the next 50 years until it was revived by the early 1970s. It is now recognized that the myenteric and submucous plexuses, referred to as the enteric nervous system (ENS), contain as many neurons as in the spinal cord. In addition to autonomy from the CNS, the ENS employs not only noradrenaline and acetylcholine but also serotonin (5-HT), ATP, peptides and nitric oxide as neurotransmitters, and controls gut movements, exocrine and endocrine secretions and the microcirculation, thus qualifying for being considered the brain of the gut. Reflexes involving the ENS may be entirely intrinsic such as that controlling peristalsis, between parts of the gut through prevertebral ganglia e.g. the enterogastric reflex, or between the gut and the CNS as examplified by the vago-vagal reflexes. Absent, defective or dysfunctional enteric neurons may result in achalasia, infantile hypertrophic pyloric stenosis, paralytic ileus, intestinal pseudo-obstruction, Hirschsprung's disease or idiopathic chronic constipation. Further, the ENS may be involved in the pathogenesis of secretory diarrhoea and inflammatory bowel disease. More research on the gut brain will deepen our understanding of the physiology and pathophysiology of the gastrointestinal tract.

Mechanism of hypergastrinaemia after nephrectomy in the rat.

Bilateral nephrectomy in the rat is followed by hypergastrinaemia and by activation of gastric histidine decarboxylase. The enzyme activity is thought to reflect the concentration of circulating gastrin. While there is general agreement that post-nephrectomy hypergastrinaemia is primarily the result of loss of renal elimination of gastrin, it remained to be determined whether gastrin secretion could be stimulated in the hypergastrinaemic state and whether it contributed to the hypergastrinaemia. Histamine, but not pentagastrin, is known to evoke gastric acid secretion in the nephrectomized rat, and histamine, but not pentagastrin, was found to lower the serum gastrin level and the gastric histidine decarboxylase activity, indicating that after nephrectomy gastrin was still secreted and that the secretion could be suppressed by increased acid output. The importance of gastrin secretion for post-nephrectomy hypergastrinaemia was assessed further by investigating the effect of nephrectomy on the serum gastrin concentration in rats previously subjected to operations that had either reduced (e.g. antrectomy) or raised (e.g. antrum exclusion) the serum gastrin concentration. Post-nephrectomy serum gastrin levels co-varied with the levels before nephrectomy. Thus, the capacity to secrete gastrin was not abolished by nephrectomy. Finally, nephrectomy greatly affected the linear correlation between the serum gastrin concentration and the gastric histidine decarboxylase activity in a manner suggesting the operation of a gastrin-independent factor capable of activating the enzyme.

Mechanism of gastric acid response to pylorus ligation: effects of nephrectomy.

In the rat nephrectomy raises the serum gastrin concentration but makes the parietal cells refractory to gastrin. Pylorus ligation stimulates the gastric acid output by a long vago-vagal reflex in innervated animals and by an intramural reflex in chronically vagotomized animals. Nephrectomy reduced the acid response to pylorus ligation in vagally intact rats but enhanced it in vagotomized rats. The acid response to pylorus ligation in all the experimental groups was inhibited by a muscarinic blocker, atropine, and by an H2-antagonist, metiamide. The serum gastrin concentration was raised by nephrectomy and by vagal denervation. Histamine mobilization from gastric endocrine cells is reflected in the activity of gastric histidine decarboxylase. The enzyme activity in pylorus-ligated innervated rats was raised by pentagastrin, atropine, and metiamide. In nephrectomized rats the basal enzyme activity was high, and it was raised further, slightly but significantly, by pentagastrin. The basal enzyme activity in pylorus-ligated rats was also quite high after vagotomy, and it was raised further by pentagastrin. After vagotomy + nephrectomy the basal enzyme activity was very high; it was not raised further by pentagastrin. It appears that both vago-vagal and intramural reflexes involve a cholinergic and a histaminergic pathway, that gastrin is not important for the neurally mediated acid response elicited by pylorus ligation, and that the postulated histaminergic pathway does not involve histamine derived from the gastric endocrine-like cells.

Role of the kidneys in elimination of glucagon, insulin, secretin and somatostatin in the rat.

Immunoreactive plasma glucagon and secretin in the rat was elevated 48 hours after nephrectomy and ureteral ligation. Since kidneys obstructed by ureteral ligation were unable to remove glucagon and secretin from the blood, renal handling of glucagon and secretin must include glomerular filtration. Insulin and somatostatin levels were significantly elevated 48 hours after nephrectomy, but not after ureteral ligation, indicating partial uptake from peritubular capillaries.

Distribution of serum proteins, red cell enzymes and haemoglobins in vitiligo.

125 Sudanese patients suffering from vitiligo were investigated for the distribution of serum proteins (haptoglobins and transferrins), red cell enzymes (acid phosphatase, 6-phosphogluconate dehydrogenase, phosphoglucomutase and glucose-6-phosphate dehydrogenase) and hemoglobins. The results were compared with the published healthy population series investigated for the same genetic markers. There was no significant association with any of the marker systems in vitiligo except glucose-6-phosphate dehydrogenase. An excess deficiency of this enzyme was observed in vitiligo patients compared to the control series.

Effects of various gastrointestinal peptides on parietal cells and endocrine cells in the oxyntic mucosa of rat stomach.

1. The effects of secretin, glucagon, cholecystokinin-pancreozymin (CCK-PZ), gastric inhibitory peptide (GIP), vasoactive intestinal peptide (VIP), somatostatin, neurotensin and enkephalin on basal, pentagastrin- and histamine-stimulated gastric acid secretion were investigated in the conscious fistula rat. 2. Glucagon and GIP were ineffective inhibitors of basal and pentagastrin-stimulated secretion. CCK-PZ stimulated acid secretion at a low dose level but at higher doses it inhibited both pentagastrin- and histamine-induced secretions. VIP was ineffective at low doses and at high doses its action was complicated by reflux of stimulated pancreatic and intestinal secretions into the stomach. Met-enkephalin inhibited histamine- but not pentagastrin-stimulated secretion. Neurotensin inhibited the response to pentagastrin but had no effect on histamine-stimulated secretion. Secretin and somatostatin were potent inhibitors of basal and pentagastrin-stimulated acid secretion with little or no effect on the response to histamine. 3. At doses completely inhibitory to pentagastrin-stimulated secretion secretin and somatostatin did not block the mobilization of gastric mucosal histamine by pentagastrin, although somatostatin caused partial competitive inhibition at lower doses of pentagastrin. Thus secretin and somatostatin inhibited pentagastrin-induced secretion neither by blocking gastric mucosal histamine mobilization nor by abolishing the direct action of histamine on the parietal cell -- findings which are inconsistent with the proposed role of histamine as the mediator of the action of gastrin on the parietal cell.

Genetic association in vitiligo: ABO, MNSs, Rhesus, Kell and Duffy blood groups.

One hundred and seventy Sudanese patients suffering from vitiligo were investigated for the distribution of A1A2BO, MNSs, Rhesus (genotypes), Kell and Duffy blood groups. The same genetic markers were investigated in Sudanese controls, consisting of two series: a published population series and a random sample of healthy blood donors. The relative frequencies of these blood groups were examined between the vitiligo patients and either or both of the control series. There was no significant association of ABO, Ss, Rhesus, Kell and Duffy blood groups in vitiligo. However, a significant association was observed with the MN system with an excess of homozygotes and of the M gene in vitiligo.

Importance of the kidneys for gastrin elimination and gastric function.

1. The gastrin concentrations in serum were elevated after nephrectomy in rats and mice indicating the importance of the kidney for elimination of gastrin in these species. In guinea-pigs and rabbits nephrectomy did not cause increased serum gastrin concentrations. In rats there was a gradual rise in the serum gastrin level up to 48 hr after bilateral nephrectomy and also after ureteral ligation. After the latter operation the concentrations of gastrin in serum were lower than after nephrectomy. Significant elevation of the gastrin level 48 hr after ureteral ligation indicates that gastrin is eliminated at least partly through glomerular filtration. The gastric histidine decarboxylase activity after nephrectomy or ureteral ligation generally reflected the concentration of circulating gastrin.2. After bilateral ureteral ligation gastric acid secretion in conscious fistula rats was uniformly inhibited with no response to pentagastrin or histamine 24 or 48 hr after the operation. After nephrectomy basal acid secretion was reduced and there was no response to pentagastrin. The response to histamine was still present, although reduced at all dose levels. Linear transformation of the dose-response curve indicated mixed inhibition. The incidence of gastric ulcer was 75% 48 hr after nephrectomy and 30% after ureteral ligation. Since basal and pentagastrin-stimulated acid secretion were unaffected by nephrectomy in rats with the upper two-thirds of the intestine removed, the intestine appears to produce factors which are responsible for the inhibition of gastric secretion.2. On the whole, the gastrin concentration in serum and gastric histidine decarboxylase activity were not increased after five-sixths nephrectomy. Gastric ulcers were seen in the rats with the highest serum urea levels; one in addition had high serum gastrin concentration and gastric histidine decarboxylase activity. Basal, pentagastrin- and histamine-stimulated acid secretion were not affected by subtotal nephrectomy. It appears that in the rat about one sixth of the renal mass is the minimum required for handling gastrin degradation and excretion.

Gastrin cell proliferation after chronic stimulation: effect of vagal denervation or gastric surgery in the rat.

Chronic stimulation of the antral gastrin cells by elevated antral pH was achieved by fundectomy, antrum exclusion, fundectomy plus antrum exclusion, antrocolic transposition, and vagal denervation plus pyloroplasty. For comparison we studied also the effects of pyloroplasty alone and of portacaval shunting. All operations that elevated the antral pH resulted in high gastrin concentrations in serum. Particularly high concentrations were observed in fundectomized rats. Vagal denervation of fundectomized or antrum excluded rats reduced the serum gastrin concentration slightly compared with the corresponding innervated animals. Portacaval shunting reduced the gastrin concentration in serum. The antral gastrin concentration was raised or unchanged following fundectomy and vagal denervation, and reduced following antrum exclusion, antrum exclusion plus vagotomy, fundectomy plus antrum exclusion, fundectomy plus vagotomy, antrocolic transposition and portacaval shunt. The gastrin cell density in the antral mucosa was raised following fundectomy, vagotomy, and fundectomy plus vagotomy, unchanged following fundectomy plus antrum exclusion and antrocolic transposition, and reduced following antrum exclusion and portacaval shunting. Ultrastructurally the gastrin (G) cells in the excluded antrum and in the antrum of fundectomized rats showed signs of secretory activity in that the granule volume density or the number of granules per unit cytoplasm was lowered. In the fundectomized rats moreover, the endoplasmic reticulum of the G cells was increased, the Golgi area enlarged and the proportion and volume density of electron dense granules greatly increased. The granule profile diameter was not affected by either antrum exclusion or fundectomy. The results on the excluded antrum indicate that elevated antral pH per se is not sufficient to produce gastrin cell proliferation. In the fundectomized rats, where the hyperlasia of antral gastrin cells was considerable, there is the added stimulus of ingested food. In fundectomized plus antrum excluded rats this stimulus is eliminated and no proliferation ensues. The passage of intestinal material, as in the rats subjected to antrocolic transposition, did not elicit gastrin cell proliferation which seems to suggest that the character of the luminal material is important. We propose therefore that gastrin cell proliferation is due to the combined stimulation of high antral pH and passage of food. Vagal innervation is not required.

Topography of somatostatin cells in the stomach of the rat: possible functional significance.

Somatostatin cells in the stomach of the rat have a characteristic shape and distribution. In the antral mucosa they occur together with gastrin cells and enterochromaffin cells at the base of the glands. In the oxyntic mucosa they are scattered along the entire glands with some predominance in the zone of parietal cells. Throughout the gastric mucosa the somatostatin cells possess long and slender processes that emerge from the base of the cell and end in club-like swellings. Such processes appear to contact a certain proportion of neighbouring gastrin cells in the antral mucosa and parietal cells in the oxyntic mucosa. Exogenous somatostatin given by intravenous infusion to conscious rats counteracted the release of gastrin stimulated by feeding, elevated antral pH or vagal excitation. Gastrin causes parietal cells to secrete HCl and endocrine cells in the oxyntic mucosa to mobilise and synthesise histamine. Somatostatin is known to block the respone of the parietal cells to gastrin. In contrast, somatostatin did not block the response of the histamine-storing endocrine cells to gastrin, perhaps because these endocrine cells lack receptors to somatostatin. Conceivably, somatostatin in the gastric mucosa has a paracrine mode of action. The observations of the present study suggest that somatostatin may affect some, but not all of the various cell types in the stomach. Under physiological conditions this selectivity may be achieved in the following ways: 1) Communication may be based on direct cell-to-cell contact. 2) Only certain cell types are supplied with somatostatin receptors.

Effect of antrum exclusion on endocrine cells of rat stomach.

1. Following antrum exclusion the serum gastrin concentration was raised and independent of the prandial state. The antral gastrin concentration and number of gastrin cells were greatly lowered. 2. The histamine content and the number of histamine-storing endocrine ('entero-chromaffin-like') cells in the oxyntic mucosa was almost doubled and the mucosal histidine decarboxylase activity was greatly elevated following antrum exclusion. 3. At the ultrastructural level both types of histamine-storing endocrine cells (ECL and A-like) were found to be enlarged and to have a reduced number of granules per unit cytoplasm. These changes are compatible with an increased secretory activity. The G (gastrin) cells were not increased in size but their granule volume density was lowered. 4. We propose that antrum exclusion results in uninhibited gastrin release causing profound changes in the histamine-storing endocrine cells of the oxyntic mucosa. The cells respond to the hypergastrinemia by an increase in functional activity (activation of histidine decarboxylase and reduction of granule volume density) as well as by an increase in number and size.

Gastrin: obligatory intermediate in the postprandial mobilization of gastric histamine in the rat.

In unoperated fasted rats, feeding raised the serum gastrin concentration, reduced the gastric mucosal histamine content and activated the gastric histidine decarboxylase. The reduction of gastric histamine and activation of histidine decarboxylase was induced also by the injection of pentagastrin. In antrectomized rats, feeding failed to produce these effects. Injection of pentagastrin, however, still lowered gastric histamine and activated gastric histidine decarboxylase. Thus, antral gastrin seems to be an obligatory mediator of the postprandial activation of histidine decarboxylase and mobilization of histamine.

Composition of the alkaline component of human gastric juice: effect of swallowed saliva and duodeno-gastric reflux.

Five patients (four with vitiligo and one with pernicious anaemia) were subjected to the histamine infusion test; there were achlorhydric while the remaining two secreted quite small amounts of acid. [Na+],[Cl-)and[alkali]were determined in the alkaline gastric juice samples (pH greater than 7.0). In order to assess the contribution of swallowed saliva the histamine test was done twice in each patient: (A) with precautions to prevent swallowing of saliva; and (B) with the patient allowed to swallow saliva freely. In each sample reflux of duodenal juice was estimated so that its contribution to the alkaline gastric aspirate could be assessed. Such reflex was absent in one patient, negligible in another, while in the remaining three patients the mean pyloric reflux amounted to no more than 8% of the observed volume. Swallowed saliva had diluting effect on [Na+] and [Cl-] but raised K+ concentration in the alkaline gastric aspirate. The comparison of alkaline gastric juice, free to an appreciable extent of salivary contamination, was shown to be relatively constant. The results are consistent with the two-component hypothesis of gastric secretion.

Effect of bilateral nephrectomy on serum gastrin concentration, gastric histamine content, histidine decarboxylase activity, and acid secretion in the rat.

Nephrectomy caused a marked increase in the concentration of circulating gastrin immunoreactivity but did not increase basal acid secretion. In normal rats, both histamine and pentagastrin stimulated gastric acid output, but after nephrectomy only histamine was effective. Histidine decarboxylase in the oxyntic mucosa was greatly activated following nephrectomy. Thus, in the nephrectomized rat gastrin (and pentagastrin) no longer evoked acid secretion, whereas it retained its ability to activate gastric histidine decarboxylase. The results suggest that the kidney is important for metabolism and excretion not only of gastrin but of humoral antagonists of gastrin-induced acid secretion as well.