Smoking and peptic ulcer in the Helicobacter pylori era.

Before the recent understanding of the central importance of Helicobacter pylori in the pathogenesis of peptic ulcer disease, smoking had been regarded as an important contributor to the cause and perpetuation of the disease. In this review, we find that (1) clinical observations indicate that smokers are more likely to develop ulcers, ulcers in smokers are more difficult to heal, and relapse of ulcer disease is more likely in smokers, (2) smoking adversely affects the gastroduodenal mucosal protective mechanisms, thus predisposing to ulcer disease, (3) smoking adversely affects gastroduodenal motility, allowing reflux of harmful duodenal contents into the stomach, (4) smokers appear to be at higher risk of becoming infected with H. pylori and this increased risk may be due to the adverse effects of smoking on antioxidants or the immune system that may interfere with the normal protection against H. pylori, and (5) once H. pylori is eradicated in smokers, they appear to be at no greater risk of peptic ulcer disease. We conclude that smoking in itself appears not to be an independent ulcerogen, but may act by augmenting the harmful effects of H. pylori, both by adversely affecting upper gastrointestinal mucosal protection and physiology and by increasing the risk of H. pylori infection. Thus, we recommend that appropriate advice to ulcer patients who smoke continues to be: stop smoking.

Is smoking still important in the pathogenesis of peptic ulcer disease?

The pathogenesis of peptic ulcer disease is multifactorial, including the effects of Helicobacter pylori, gastric acid, pepsin, gastroduodenal motility, smoking and nicotine, and the complex interaction of an array of other so-called aggressive and protective factors. Since the discovery and acceptance of H. pylori as a major etiologic agent in peptic ulcer disease, the role of smoking has received less attention. Smokers are more likely to develop ulcers, ulcers in smokers are more difficult to heal, and ulcer relapse is more likely in smokers. These clinical observations may be explained by the adverse effects that smoking has on mucosal aggressive and protective factors. Of the aggressive factors, smoking appears to have no consistent effect on acid secretion. However, smoking impairs the therapeutic effects of histamine-2 antagonists, may stimulate pepsin secretion, promotes reflux of duodenal contents into the stomach, increases the risk for and harmful effects of H. pylori, and increases production of free radicals, vasopressin, secretion by the pituitary, secretion of endothelin by the gastric mucosa, and production of platelet activating factor. Smoking also affects the mucosal protective mechanisms. It decreases gastric mucosal blood flow and inhibits gastric mucous secretion, gastric prostaglandin generation, salivary epidermal growth factor secretion, duodenal mucosal bicarbonate secretion, and pancreatic bicarbonate secretion. These adverse effects of smoking on aggressive and protective factors quality it as an important contributor to the pathogenesis of peptic ulcer disease and indicate that smoking plays a significant facilitative role in the development and maintenance of peptic ulcer disease.

Pharmacologic prevention of colonic neoplasms. Effects of calcium, vitamins, omega fatty acids, and nonsteroidal anti-inflammatory drugs.

Dietary supplements of calcium, vitamins A, C, and E, carotenoids, and omega-3 fatty acids can reduce the yield of experimental cancers in animals and reverse the pattern of abnormal epithelial proliferation in animals and humans. Epidemiological studies indicate that diets containing high amounts of these agents convey a protective effect against the development of colon cancer. Moreover, regular aspirin use in humans appears to reduce the risk of colon cancer and sulindac causes regression of polyps in patients with familial polyposis. These agents are promising for the prevention of human colorectal cancer, but their efficacy has not yet been shown in prospective, controlled trials. Thus, although it is tempting to speculate that in the future we may treat our patients who have a predisposition to colon polyps and cancer, or even healthy people at average risk, with such ordinary supplements as calcium, vitamins, fish oil, or aspirin, such advice at this time is premature.

A review of gastrointestinal epithelial renewal and its relevance to the development of adenocarcinomas of the gastrointestinal tract.

Renewal of the gastrointestinal (GI) epithelium fulfills the normal functions of maintaining the integrity of the mucosa, repairing mucosal injury, and replenishing the specialized cells of the epithelium. Alterations in epithelial renewal also are intimately involved in transformation of the epithelium to benign and malignant neoplasms. Certain abnormalities in epithelial proliferation, including an increase in the rate of proliferation and expansion of proliferating cells beyond the normal zone of proliferation, are closely linked to the predisposition for and frank development of GI cancer. These abnormalities are common to all human premalignant conditions studied, including Barrett's epithelium, chronic gastritis, inflammatory bowel disease, and colon polyps; they also occur in experimental carcinogenesis. The same proliferative abnormalities have also been observed in some relatives of patients with colon neoplasms who themselves do not have any colon polyps or cancer. Several agents, including calcium, vitamins A, C, and E, and omega-3 fatty acids, have been shown to reverse the abnormal proliferation under some laboratory and clinical conditions. Moreover, some nonsteroidal anti-inflammatory drugs appear to decrease the size of colon polyps in familial polyposis and to reduce the risk for colon cancer in the general population. We await further clinical trials that will indicate whether such ordinary supplements as calcium, vitamins, fish oil, or aspirin have a role in the treatment of patients with premalignant conditions of the gastrointestinal tract.

Nicotine has no effect on rat gastric mucosal prostaglandin generation in vitro.

Previous studies have shown that cigarette smoking depresses prostaglandin generation by human gastric mucosa, but the component of smoke that is responsible for that action is not known. To investigate whether nicotine has a direct effect on gastric mucosal prostaglandin generation, we performed the following study. Eight rats were sacrificed and the stomachs removed. Using a biopsy forceps, small pieces of gastric mucosa were resected and placed in incubation vials containing either buffered Krebs solution alone (control), Krebs solution plus indomethacin (5 micrograms/ml), or Krebs solution plus one of several concentrations of nicotine ditartrate (10, 100, 500, 1000 ng/ml). The nicotine concentrations we used ranged below and above the plasma nicotine concentrations of smokers shortly after smoking cigarettes. Three separate incubations of gastric mucosa were performed per experimental group from each animal. After 30 min of incubation, prostaglandin E2 and 6-keto-prostaglandin F1 alpha concentrations in the incubation medium were measured by radioimmunoassay. We found that nicotine at any concentration tested had no effect on the generation of prostaglandin E2 and 6-keto-prostaglandin F1 alpha by rat gastric mucosa. Thus, this study indicates that, if nicotine is involved in the depression of prostaglandin generation in the gastric mucosa of smokers, its role is an indirect one and not by direct action on the gastric mucosa.

Endoscopy in gastrointestinal bleeding. Are we beginning to realize the dream?

Fiberoptic endoscopy has enabled clinicians to make accurate diagnoses of the cause of acute upper gastrointestinal (GI) bleeding, but, contrary to expectation, that information by itself has not led to improved morbidity or mortality in patients with upper GI bleeding. However, the identification of the so-called stigmata of recent hemorrhage and the subsequent development of effective endoscopic treatments of bleeding lesions have provided hope, based on evidence from numerous clinical trials, that some patients with acute upper GI bleeding will benefit from endoscopic intervention. Injection sclerotherapy, now standard treatment for bleeding esophageal varices, is capable of controlling acute variceal bleeding and is equally effective or better than surgical procedures such as portosystemic shunts and esophageal transection. The question remains whether sclerotherapy of esophageal varices improves survival. With regard to therapeutic endoscopy of bleeding ulcers, multipolar electrocoagulation, laser photocoagulation, and injection of various agents all may be effective and beneficial. All of these methods appear to be capable of controlling acute bleeding and may improve survival, but because of the safety and low cost of injection therapy, that treatment ultimately may be preferred.

Hydrocortisone has a biphasic effect on rat gastric mucosal prostaglandin generation in vivo: inhibition at low doses, stimulation at high doses.

To determine the effect of different doses of hydrocortisone sodium succinate (HC) on rat gastric mucosal prostaglandin synthesis, two experiments were performed. In the first experiment, 20 male Lewis rats were divided into 4 groups of 5 rats each and gavaged either with 2 ml of water (control) or different concentrations of HC (10 mg/ml, 100 mg/ml and 500 mg/ml). In the second experiment in a similar design, lower doses of HC were used (water, 0.1 mg/ml, 0.50 mg/ml and 5.0 mg/ml). The rats were killed after 1 h and three 3 x 3 mm pieces of gastric tissue were removed from each rat and incubated for the determination of prostaglandin E2 and 6-keto-prostaglandin F1 alpha accumulation in the medium measured by radioimmunoassay. At low doses HC inhibits rat gastric mucosal prostaglandin synthesis whereas at higher doses HC stimulates it. This biphasic effect of HC on gastric mucosal prostaglandin synthesis may help explain its role in ulcerogenesis.

Epithelial renewal in premalignant conditions of the gastrointestinal tract: a review.

The constant rapid renewal of the epithelium of the gastrointestinal (GI) tract is important in the development of neoplasms that are derived from the epithelium as well as in maintaining the functional integrity of the mucosa. An abnormality of epithelial proliferation, characterized by an increase in numbers of proliferating cells and expansion of the proliferative zone, is common to all human premalignant conditions of the GI tract that have been studied, including Barrett's epithelium, chronic gastritis, ulcerative colitis, and colonic polyps, and is a consistent observation after the use of experimental carcinogens, such as N-methyl-N-amylnitrosamine and N-methyl-N'-nitro-N-nitrosoguanidine. These abnormalities also have been observed in some relatives of patients with colonic polyps or cancers who themselves do not have any demonstrable colonic lesion. Calcium, vitamins A, C, and E, and other agents have been shown to reverse the abnormalities in proliferation in some experimental and clinical conditions, which raises the question of whether some of these agents can be used to reduce the risk of development of cancer in patients with known premalignant conditions of the GI tract.

Effects of sucralfate, lansoprazole, and cimetidine on the delayed healing by hydrocortisone sodium phosphate of chronic gastric ulcers in the rat.

We have previously shown that chronic sucralfate ingestion stimulates gastric epithelial proliferation in rats, which may explain one of the beneficial effects of sucralfate in healing of peptic ulcers. In a separate study, we have found that chronic steroid administration delays the healing of experimental gastric ulcers in rats. This study was designed to test the beneficial effects of sucralfate, cimetidine, and lansoprazole (AG-1749, a new proton pump inhibitor), on the delayed healing by steroids in rat chronic gastric ulcers. Chronic gastric ulcers were produced in male Wistar rats, weighing 180 g, by the application of 100% acetic acid. The rats were randomly divided into five groups; (1) control, (2) vehicle alone, (3) 10 mg/kg lansoprazole, (4) 500 mg/kg sucralfate, and (5) 100 mg/kg cimetidine. Except for controls, all rats received daily intraperitoneal injections of 2.5 mg/kg hydrocortisone sodium phosphate. Tested drugs were administered intragastrically (lansoprazole and sucralfate) or intraperitoneally (cimetidine) twice a day for 2 weeks. Rats were sacrificed 14 days later and ulcer size was measured. Chronic administration of hydrocortisone sodium phosphate resulted in a significant delay of ulcer healing induced by acetic acid. Treatment with either lansoprazole or sucralfate abolished the deleterious effect of steroids, whereas cimetidine had no effect. These results indicate that lansoprazole and sucralfate overcome the delayed healing by steroids of chronic gastric ulcers in the rat.

Gastroduodenal mucosal prostaglandin generation in patients with Helicobacter pylori before and after treatment with bismuth subsalicylate.

To determine whether Helicobacter pylori has an effect on gastroduodenal mucosal prostaglandin generation, mucosal biopsies were obtained from the gastric body, antrum, and duodenal bulb of 30 patients who were undergoing upper gastrointestinal endoscopy for clinical indications. One biopsy from the gastric body and one from the antrum were tested for urease activity (urea broth) and one biopsy from each area including the duodenum was processed for histology. Two other biopsies form each area were incubated and the accumulation of prostaglandin E2 and 6-keto prostaglandin F1 alpha in the incubation medium was measured by radioimmunoassay. Twelve of the 17 H. pylori-positive patients and seven of the 13 H. pylori-negative patients agreed to take bismuth subsalicylate (Pepto-Bismol) two tablets four times a day for four weeks. One week after treatment, these patients again underwent endoscopy and the above studies. This study indicates that: (1) mucosal PGE2 generation may be increased in the duodenum, gastric body, and antrum in H. pylori-positive patients compared to H. pylori-negative patients, and (2) treatment with bismuth subsalicylate for four weeks results in reduction of mucosal PGE2 in the duodenum, gastric body, and antrum of H. pylori-positive patients and fails to eradicate H. pylori or reduce gastric inflammation.

Epithelial renewal in protection and repair of gastroduodenal mucosa.

The constant, rapid renewal of the gastroduodenal epithelium is an important mechanism of mucosal protection because it maintains the functional integrity of the epithelium. It also is necessary for the repair of mucosal injury. Aspirin, indomethacin, and ethanol all have been shown to stimulate epithelial proliferation in the experimental setting. The stimulatory effects of these agents may be a compensatory reaction to mild injury and may contribute to the process of mucosal adaptation. On the other hand, corticosteroids, physiologic stress, and smoking appear to depress epithelial proliferation, which could render the mucosa susceptible to the effects of other ulcerogens as well as retard the healing of existing mucosal lesions. Epithelial proliferation in mucosa adjacent to active duodenal ulcers as well as from nonulcerated duodenitis is increased when compared to normal-appearing mucosa. This stimulation of epithelial proliferation may be caused by inflammation; it is not known whether ulcer patients have a defect in epithelial proliferation that precedes ulceration. Although prostaglandins (PGs) protect ulceration. Although prostaglandins (PGs) protect the gastroduodenal mucosa, the weight of evidence indicates that PGs do not have a primary effect on epithelial proliferation but rather retard senescence and loss of epithelial cells. The result is thickening of the mucosa, which may contribute to the protective effects of PGs. Ulcerogenic agents or conditions may either depress epithelial proliferation, which predisposes to ulceration or the ulcerogenic effects of other ulcerogens, or result in a hyperproliferative response, which may contribute to the process of mucosal adaptation and protection.