Challenges in acid/peptic disorders: a symposium overview.

Before 1977, the treatment of peptic ulcer disease consisted primarily of dietary, antacid, and anticholinergic programmes. There were heated controversies regarding rigid vs. liberal ulcer diets, a variety of antacids and dosing patterns to choose from, and conflicting claims over the benefit of various anticholinergic therapies. It was hoped that the dramatic introduction of the H2-receptor antagonists would simplify our approach to the treatment of peptic ulcer and reflux oesophagitis. Standard doses of H2-receptor antagonists are effective for acid/peptic disorders, yet it has become clear that some subsets of patients present special management problems, including recurrent ulcers, non-steroidal anti-inflammatory drug (NSAID)-induced disease, stress ulcers, and refractory oesophagitis. New regimens, such as maintenance therapy and once-daily nocturnal dosing, have been indicated for peptic ulcer disease. New drugs have been introduced, such as sucralfate, misoprostol, and omeprazole, each with a different mechanism of action. Therefore, while we have learned considerably more about the pathogenesis of peptic disease, treatment decisions have become more complicated. The Transatlantic Conference on Acid/Peptic Disorders was held on 19-21 January 1990, in Wesley Chapel, Florida. A faculty from the United Kingdom, the United States, and Canada reviewed pathophysiology and the role of pharmacologic agents in the treatment of acid/peptic disorders and outlined clinically useful treatment strategies. The conference was organized into five segments: acid suppression and ulcer healing; acid suppression and control of reflux disease; NSAID-induced ulceration; stress ulceration, rationale for control of rebleeding, and drug interactions; and controversies. The proceedings of the symposium are presented in this supplement.

Gastrin's trophic effect in the colon: identification of a signaling pathway mediated by protein kinase C.

In previous studies we have reported that gastrin exerts a trophic effect on rat colonic epithelial cells in vitro. The effect of gastrin appeared to be mediated through a protein kinase C mechanism. In this study, we have characterized the role of protein kinase C in the gastrin-induced stimulation. Gastrin, in a time- and dose-dependent manner, increased protein kinase C translocation from the cytosol to the membrane, an index of enzyme activation. Maximum translocation occurred in 1 to 2 min following exposure to gastrin (10(-8) M), before declining back to baseline level within 5 min. Gastrin did not change total protein kinase C activity in the colonic cells. Staurosporine, an inhibitor of protein kinase C, totally abolished the basal as well as the gastrin-stimulated activity of protein kinase C. The tumor promoter phorbol 12-myristate 13-acetate also stimulated colonic epithelial protein kinase C. However, prolonged treatment of cells with phorbol inhibited their subsequent response to gastrin stimulation. The response to gastrin was also prevented by the gastrin receptor antagonist proglumide. These observations suggest that protein kinase C mediates the stimulatory effect of gastrin on colonic epithelial cells, possibly through a receptor mechanism.

Gastrin induction of mRNA expression in rat colonic epithelium in vitro.

A newly developed system of isolated rat colonic epithelial cells was utilized for a comprehensive study of protein synthesis influenced by gastrin. We found that synthetic human gastrin (0.01-100 nM) increased the incorporation of [35S]methionine into proteins within 2 hours. Peak incorporation was observed with 10 nM gastrin to more than two-fold above maintenance levels. Actinomycin-D (10 micrograms/ml) inhibited the stimulated increases in total protein synthesis indicating that the peptide's trophic effect was mediated by the synthesis of new mRNA species. The effect of gastrin was comparably stronger than the one induced by the mitogen bombesin (1 nM). However, bombesin, a neuromodulator of gastrin release, did not produce an additive effect beyond that of gastrin on total protein synthesis. Gastrin stimulated the synthesis of many polypeptides resolved on two-dimensional polyacrylamide gel, an indicator of gastrin's influence on the expression of various mRNA species. Some of these polypeptides may be used as markers in investigating colonic epithelial response to gastrin.

Helicobacter pylori: aggressor or innocent bystander?

Helicobacter pylori seeks gastric mucosa, whether found in the stomach, duodenum, or Barrett's esophagus. Definitive diagnosis can be secured by appropriate stains of mucosal biopsies and culture, but the rapid urease test, breath isotope studies, and serologic testing are also useful. The frequency of colonization increases with advancing age, but infection occurs earlier in underdeveloped countries. Although the reservoir is uncertain, water or food transmission seems likely. There is sufficient evidence to assign an etiologic role to the bacteria in the causation of type B antral gastritis. H. pylori is found in areas of gastric metaplasia within the duodenum and is associated with duodenitis. Although acute infection leads to hypochlorhydria, chronic colonization has little effect on acid secretion. Studies have thus far failed to establish a convincing relationship between H. pylori and nonulcer dyspepsia, although the bacteria may play a role in selected patients. H. pylori is found in association with most idiopathic gastric and duodenal ulcers, but it is unclear as to whether the bacteria plays a causative or permissive role. The organism has a predilection for intercellular spaces and the mucous layer, thus affording relative isolation from luminally active antibiotics. Monotherapy with bismuth preparations transiently eliminates the bacteria, but recolonization is rapid, probably due to regrowth of sequestered organisms. A combination of metronidazole, bismuth, and tetracycline (or amoxicillin) affords the best eradication rate, but the potential side effects of this program should be considered. The present therapy of duodenal ulcer disease is effective and without significant risk. Treatment of H. pylori should be reserved for those patients who relapse on adequate maintenance therapy. If a safe and effective antibiotic becomes available, more frequent testing and earlier treatment intervention may become more attractive. H. pylori is probably an "innocent bystander" for most patients, but the bacteria may sufficiently impair the defenses of the antral and duodenal mucosa to facilitate the development and relapse of ulcer disease in subsets of patients.

Hydrogen peroxide-induced alterations in prostaglandin secretion in the rat colon in vitro.

Although the specific cause(s) of inflammatory bowel diseases (IBD) has not been identified, one theory suggests ischemia as the early event that occurs in IBD and reperfusion causes sustained release of oxyradicals, leading to inflammation and ulceration. In this study, we have confirmed that H2O2 in the concentration seen during ischemia/reperfusion is primarily responsible for cellular membrane damage in the rat colonic fragments in vitro. Hydrogen peroxide caused a time and dose-dependent increase in 6-keto-PGF1 alpha and TXB2 release. Hydrogen peroxide-stimulated 6-keto-PGF1 alpha release was blocked (50%) by phospholipase A2 (PLA2) inhibitors quinacrine and dimethyleicosadienoic acid at 5 min. Hydrogen peroxide-stimulated 6-keto-PGF1 alpha release was completely blocked by indomethacin, significantly blocked (69%) by nordihydroguiaretic acid, and completely blocked by catalase. Superoxide dismutase and uric acid failed to inhibit H2O2-stimulated 6-keto-PGF1 alpha release. Endogenous catalase inhibitors 3-aminotriazole and sodium azide further enhanced the release of 6-keto-PGF1 alpha stimulated by H2O2 by 29% and 73%, respectively. Xanthine-xanthine oxidase also increased 6-keto-PGF1 alpha release from the fragments by 110%. This release was not inhibited by superoxide dismutase and uric acid, but was completely inhibited by catalase. These studies suggest a direct effect of H2O2 on colonic fragments leading to submicroscopic cellular membrane damage and excess prostanoid production utilizing a PLA2/cyclooxygenase and catalase-sensitive pathway without the formation of toxic hydroxyl ions. The quick release of 6-keto-PGF1 alpha also suggests an early manifestation of H2O2-induced damage in rat colonic fragments.

Clinical intestinal gas syndromes.

Belching, flatulence, abdominal distention, and gas pains are common symptoms that may stimulate concern for the patient and from the physician. An understanding of the pathophysiology of intestinal gas syndromes should permit a more focused diagnostic and therapeutic approach.

Consultant strategies for the gastroenterologist.

Effective communication skills and the ability to respond to the needs of referring physicians are critical for the maintenance and enhancement of a referral base. One challenge is to determine the reason for the consultation and to respond to the referring physician's interests. The consultation letter should be formatted effectively and the "turn-around time" should be as brief as possible, perhaps by fax as well as mail. Prioritizing the differential diagnosis and diagnostic studies can be helpful to the referring physician. Strategies should be developed to address procedural referrals you may believe are inappropriate. A decision should be made as to whether the consultant or the primary care physician informs the patient of a serious disease diagnosis. Referral guidelines should be developed to assist primary care physicians to determine when a patient should be referred to the gastroenterologist or other specialist. Receptionists should avoid turning away new patients because of a "full schedule" and must determine if other arrangements can be made. A proper response to "hallway consultations" by referring physicians is important. Consultants should make efforts to increase their visibility in the medical community, either by newsletter or lectures to the medical staff. Every effort should be made to avoid speaking disparagingly about other physicians. Consultant strategies should be taught to house staff and fellows in a formal lecture format, in the outpatient clinics, and on hospital rounds.

Management of NSAID-induced ulcer disease.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of gastric and duodenal ulcers, especially in patients with previous ulcer disease, heavy smokers, patients who are taking steroids and those with other illnesses. In patients at risk for gastroduodenal complications, prophylactic therapy with misoprostol or an H2-receptor antagonist should be considered. If ulcers occur during NSAID therapy, the anti-inflammatory drug should be discontinued and standard ulcer-healing therapy instituted. If NSAID therapy must be continued, ulcer healing may be prolonged.

Pharmacologic therapy for inflammatory bowel disease.

The pharmacologic management of ulcerative colitis and Crohn's disease is usually carried out in a stepwise fashion. Initially, oral sulfasalazine or 5-aminosalicylic acid (5-ASA) products are given and, for patients with rectal disease, treatment may include topical therapy with either 5-ASA enemas or hydrocortisone suppositories. Patients with more active inflammatory disorders may also require oral corticosteroid therapy. Patients with fulminant disease may require intravenous steroids and antibiotic therapy. If frequent relapses prevent discontinuation or significant reduction of prednisone therapy, azathioprine or 6-mercaptopurine may offer benefit as steroid-sparing agents. Also, intravenous cyclosporine has proved useful in patients with fulminant inflammatory bowel disease that is unresponsive to other therapy. Metronidazole has value in the treatment of perianal disease secondary to Crohn's disease. Balancing the risks and benefits of single or combination therapy is an ongoing challenge in patients with inflammatory bowel disease.

Mucoepidermoid (adenosquamous) carcinoma arising in Barrett's esophagus.

A case of mucoepidermoid or adenosquamous carcinoma arising from the mucous epithelium of a Barrett's esophagus is presented. Immunohistologic examination demonstrated carcinoembryonic antigen (CEA) in both the glandular and squamous components, but keratin only in the latter. Although mucoepidermoid carcinoma of the esophagus is believed to arise from submucosal glands, heterotopic gastric surface epithelium may also give rise to this uncommon neoplasm.

Omeprazole: a new approach to gastric acid suppression.

Omeprazole, one of a new group of antisecretory drugs, is a substituted benzimidazole that does not exhibit the anticholinergic or histamine H2 antagonistic properties of drugs such as cimetidine. This agent suppresses gastric acid secretion by inhibiting the proton pump mechanism, thereby blocking the final step of acid secretion. Omeprazole is significantly more effective than the histamine H2 receptor antagonists in eliminating acid secretion; thus, it may be beneficial in patients who are resistant to these agents. Omeprazole is indicated for severe erosive esophagitis, gastroesophageal reflux disease that does not respond to H2 receptor antagonists, and hypersecretory diseases such as Zollinger-Ellison syndrome and systemic mastocytosis. Because of the theoretic risk of carcinogenesis, short-term therapy is recommended, although long-term therapy is required for hypersecretory diseases.

Azathioprine reduces extravasation and neutrophil trafficking in immune complex-mediated inflammation in the rat colon.

Azathioprine (AZ) has been used in the treatment of refractory inflammatory bowel disease. The mechanism by which AZ decrease colonic inflammation is not known. It is alluded that AZ may be effective in the maintenance of remission. We examined whether AZ in non-immunosuppressive doses reduces extravasation and neutrophil trafficking in a rat model of colonic inflammation. Rats were treated with I.P. injection of AZ (1 mg/kg) for 6 weeks. At the end of 2 and 6 weeks rats were injected I.V. immune complex and on the following day the proximal colon was perfused with 2.5% formaldehyde (local irritant 3 ml/hour for 5 mins). Extravasation was measured by Evans' blue technique and neutrophil concentration in the tissue was determined by measuring myeloperoxidase (MPO). AZ did not inhibit extravasation and MPO after 2 weeks of therapy. However, after 6 weeks, AZ reduced extravasation to 20 +/- 2 micrograms/gm compared to untreated animals (51 +/- 6 micrograms/gm tissue) and MPO levels to 0.3 +/- 13 compared to untreated rats (0.8 +/- 0.32 mU/gm). There was a good correlation between extravasation and MPO levels. These results suggest that long-term treatment with AZ may prevent extravasation and cause reduction in neutrophil trafficking. Such an effect may be beneficial for maintaining remission in IBD.

Bile acid and pancreatic trypsin outputs are parallel during intraduodenal infusion of essential amino acids.

There is disagreement as to whether contraction of the gallbladder occurs simultaneously with secretion of pancreatic enzymes during food ingestion. One study that employed exogenous cholecystokinin (CCK) alone showed dissociation of total bile acids (TBA) and trypsin outputs, while another study that employed exogenous CCK plus secretin showed parallel outputs of TBA and trypsin. Since previous studies have suggested that intraduodenal infusion of essential amino acids (EAA) evokes pancreaticobiliary secretion similar to that observed with food ingestion, we infused increasing doses of EAA intraduodenally in 10 subjects with intact gallbladder and in 10 subjects with previous cholecystectomy and measured total bile acids and trypsin outputs serially. In subjects with intact gallbladder, increasing molar doses of EAA induced parallel increases of TBA and trypsin outputs. In subjects with previous cholecystectomy trypsin outputs during infusion of EAA were similar to subjects with intact gallbladder, but their TBA outputs remained constant during the entire infusion period. Serial concentrations of plasma secretin did not change during intraduodenal infusion of EAA. These observations suggest that the gallbladder empties bile in concert with secretion of pancreatic enzymes following food ingestion.

Simultaneous measurement of basal pancreatic, gastric acid secretion, plasma gastrin, and secretin during smoking.

The effect of smoking one unfiltered cigarette every 15 min for 1 hr on basal gastric acid and pancreatic secretion was studied in 10 subjects with a history of duodenal ulcer and 10 without duodenal ulcer. Smoking induced a transient rise of basal acid output followed by a slight decrease. This effect was more pronounced in the duodenal ulcer group. Smoking markedly inhibited fluid and bicarbonate secretion during the smoking period. The bicarbonate and fluid secretion returned to control levels within 30 to 60 min in the ulcer group and in 60 to 90 min in the nonulcer group. There was no difference in the degree of inhibition of pancreatic secretion between the two groups. Immunoreactive gastrin and secretin in the peripheral venous blood did not change significantly during smoking. The degree of inhibition of basal pancreatic secretion correlated well with the plasma concentrations of nicotine. These observations indicate that smoking in the fasting state induces alterations of basal gastric and pancreatic secretions which are not related to changes in plasma gastrin and secretin concentration, but to plasma concentrations of nicotine. The implication of this study in relation to a possible causal association between cigarette smoking and peptic ulcer disease is discussed.

Serial pH changes in the duodenal bulb during smoking.

The effect of smoking on the pH of the duodenal bulb was studied in 10 normosecretors and 10 hypersecretors using a Beckman pH electrode. The pH was monitored during three study periods, basal, smoking, and postsmoking, of 1 hr each. The pH remained below 3.5 significantly longer during the smoking period compared to the basal period for both groups. The bulbar pH remained under 3.5 during the smoking period longer in the hypersecretor group compared to the normosecretor group (60 versus 20%). Hypersecretors who were smokers exhibited acidic bulbar pH values longer and more consistently than hypersecretor-nonsmokers during smoking. In 5 hypersecretors with data for both bulbar pH and bicarbonate output, inhibition of bicarbonate output during smoking was generally associated with acidic pH values in the bulb. These observations suggest that the association between cigarette smoking and peptic ulcer disease may be attributable to, in part, the persistently acidic pH values in the duodenal bulb during smoking. This study further suggests that the degree and the duration of acidification of the duodenal bulb during smoking are influenced by the secretory and the smoking status of the subject.

Development of lymphoma in patients with Crohn disease.

The authors report 3 cases of lymphoma developing in patients with Crohn disease. Neither a cause-and-effect relationship nor a common etiology could be proven.