Among the advances made in the field of gastroenterology in the past year, advances in the knowledge and treatment of common upper gastrointestinal symptoms have been the most prominent. The long-term use of proton-pump inhibitors was found to be effective, and various regimens against Helicobacter pylori disease were expanded. The causes of nonulcer dyspepsia were described; even after exhaustive work-ups, however, a third of patients still had "idiopathic" dyspepsia. Advances also took place in the prevention of gallstones, the treatment of ulcerative colitis, the prevention of colon cancer in women, and the use of antibiotics in necrotizing pancreatitis.

Gastroesophageal Reflux Disease

Seven percent of U.S. adults have symptoms of gastroesophageal reflux disease at least once daily. More than half of patients with reflux disease have mild sporadic symptoms and use over-the-counter antacids or histamine blockers. About 20% to 30% of patients frequently have symptoms and consult their primary care physicians about treatment. About 10% to 15% of patients have chronic, persistent symptoms with or without complications and are usually referred to a gastroenterologist.

The major factor contributing to gastroesophageal reflux disease is inappropriate relaxation of the lower esophageal sphincter. Secondary factors include poor esophageal clearance of acid, delayed gastric emptying, and the potency of refluxate. It is not generally appreciated that several medications and foods, such as alcohol, caffeine, chocolate, peppermint, fried foods, onions, and fatty foods, may reduce lower esophageal sphincter pressure and delay gastric emptying, thereby facilitating reflux disease. Several beverages have a very acidic pH and can aggravate symptoms of reflux in patients with underlying esophagitis. Such beverages include Coca Cola and Pepsi Cola (each of which has a pH of 2.5), red wine (pH, 3.25), and orange juice (pH, 3.5).

It is important to keep a detailed drug history of patients with gastroesophageal reflux disease because several drugs-including anticholinergic agents, tricyclic antidepressant agents, calcium channel blockers, ß-agonists, drugs containing L-dopa, narcotics, prostaglandins, progesterone, and theophylline-reduce lower esophageal sphincter pressure. Patients with gastroesophageal reflux disease and underlying, endoscopically verified reflux esophagitis have a high rate of relapse within 1 year of discontinuing antireflux therapy. The search for optimal treatment regimens continues.

Proton-Pump Inhibitor Was Effective over the Long Term

Vigneri S, Termini R, Leandro G, Badalamenti S, Pantalena M, Savarino V, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med. 1995; 333:1106-10.

Vigneri and colleagues compared single-drug regimens (cisapride, ranitidine, and omeprazole) and two combined drug regimens (ranitidine plus cisapride and omeprazole plus cisapride) in patients with erosive reflux esophagitis. Seventy-five patients with endoscopically proven reflux esophagitis were initially treated with omeprazole, 40 mg daily for 8 weeks, to promote healing. Patients were then assigned to receive one of five treatment regimens. Endoscopy was repeated at 6 and 12 months.

The following are the numbers of patients receiving each drug who remained in remission at 12 months: cisapride, 19 of 36 (54%); ranitidine, 17 of 39 (49%); omeprazole, 28 of 35 (80%); ranitidine plus cisapride, 23 of 35 (66%); and omeprazole plus cisapride, 31 of 35 (89%). These findings clearly indicate that omeprazole alone or in combination with cisapride was more effective than ranitidine alone or cisapride alone. Omeprazole combined with cisapride was only marginally more effective than omeprazole alone.

These results indicate that protein-pump inhibitors, such as omeprazole, are effective in the long-term maintenance of remission in patients with endoscopically verified reflux esophagitis.

Helicobacter pylori Infection

More than 90% of duodenal ulcers and 75% of gastric ulcers are associated with H. pylori infection. The average annual recurrence rate of duodenal ulcer after eradication of H. pylori is 2% (range, 0% to 6%); this rate underscores the importance of eliminating this pathogen in patients with peptic ulcer disease.

Noninvasive Tests Effectively Diagnosed Helicobacter pylori Infection

Cutler AF, Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology. 1995; 109:136-41.

Cutler and colleagues compared the characteristics of several currently available tests used to diagnose H. pylori infection. A total of 268 patients were tested for H. pylori infection by both invasive and noninvasive tests. Because no gold standard is available for diagnosis, the standard for comparison was at least four positive test results.

The study findings are shown in Table 1. Two noninvasive tests (the [C₁₃] urea breath test and measurement of serum IgG H. pylori antibody titers) had sensitivity and specificity values similar to those of invasive tests, especially the Warthin-Starry stain. Thus, the noninvasive urea breath test or a high titer of antibody to H. pylori IgG is as accurate for predicting H. pylori status in untreated patients as an invasive test.

Quadruple Therapy Was More Effective against Helicobacter pylori

de Boer W, Driessen W, Jansz A, Tytgat G. Effect of acid suppression on efficacy of treatment for Helicobacter pylori infection. Lancet. 1995; 345:817-20.

Several treatments for H. pylori infection have been described. Popular regimens currently include quadruple therapy comprising omeprazole plus bismuth, metronidazole, and tetracycline or triple therapy consisting of metronidazole, omeprazole, and clarithromycin (so-called MOC therapy).

The authors sought to determine whether omeprazole would improve the results of triple therapy in eradicating H. pylori. A total of 108 consecutive patients with biopsy-proven H. pylori peptic ulcer disease at a referral center were randomly assigned to one of two groups. One group received the following drugs for 7 days: bismuth, 120 mg four times daily; tetracycline, 500 mg four times daily; and metronidazole, 500 mg three times daily. The experimental group received the same regimen plus omeprazole, 20 mg twice daily, for 10 days. Endoscopic biopsies and cultures were done 4 to 6 weeks after initiation of therapy.

Helicobacter pylori was eradicated in 98.1% of patients receiving quadruple therapy and in 83.3% of patients receiving antibiotics alone. The incidence of side effects was only slightly higher in the quadruple therapy group (25.9% in the antibiotic group and 29.6% in the quadruple therapy group). More recent studies by de Boer and colleagues have indicated that omeprazole given for 7 days and bismuth, metronidazole, or tetracycline given for just 4 days is also effective in eradicating H. pylori. The shorter course is appropriate if the H. pylori strain is sensitive to metronidazole, but the 7-day regimen is more established. Trials are under way to define regimens that might be as efficacious and more acceptable to patients.

Nonulcerative Dyspepsia

Dyspepsia consists of episodic, recurrent, or persistent abdominal pain or discomfort affecting the upper abdomen. Nonulcerative dyspepsia is a complex and confusing disorder defined by nondiagnostic esophagoduodenostomy. The following are the three subsets of nonulcerative dyspepsia: 1) gastroesophageal reflux-type dyspepsia; 2) ulcer-like symptoms; and 3) dysmotility-type dyspepsia associated with postprandial bloating, distention, and early satiety. All three types of nonulcerative dyspepsia are present in as many as a third of patients with the disorder.

Nonulcerative Dyspepsia Was Commonly "Idiopathic"

Stanghellini V, Tosetti C, Paternico A, Barbara G, Morselli-Labate AM, Monetti N, et al. Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology. 1996; 110:1036-42.

Stanghellini and colleagues evaluated 1057 consecutive patients referred for chronic dyspepsia to assess the cause of the symptoms. All patients had upper gastrointestinal endoscopy. Table 2 lists the final diagnoses of these patients. The most frequent diagnosis was functional or idiopathic dyspepsia, which was found in 32.5% of the patients. Peptic ulcer was found in 21.4% of patients, esophagitis in 9.4%, and gastric cancer in 0.6%.

Possible causes of endoscopically verified functional nonulcerative dyspepsia include the following: 1) abnormal sensation or perception, 2) acid peptic injury, 3) duodenal-gastric reflux, 4) H. pylori-induced gastritis, 5) dysmotility, and 6) psychopathology. No convincing evidence suggests that eradication of H. pylori in this setting alleviates symptoms.

Recent studies suggest that dysmotility may be an especially important pathogenic factor. Clinical trials have suggested that such pro-motility drugs as cisapride may be effective in the subset of patients with nonulcerative dyspepsia that is predominantly characterized by dysmotility.

In patients with dyspepsia, certain alarm signals should prompt consideration for a more detailed work-up. Such signals include anorexia; weight loss; such obstructive symptoms as nausea, vomiting, and early satiety; positive results on a fecal occult blood test; anemia; a family history of peptic ulcer disease; dysphagia; and abnormal findings on physical examination. If alarm signals are present, the work-up of dyspepsia should include esophagogastroduodenoscopy, a gastric emptying study, and such imaging studies as ultrasonography and computed tomography. If patients with gastroesophageal reflux-type dyspepsia have an incomplete response to therapy, 24-hour pH monitoring and esophageal motility studies may help.

Lactose Intolerance

Once humans are weaned from the breast, lactase levels in the gut tend to decrease because of an inherited autosomal dominant gene. Persons of northern European descent tend to retain fairly high levels of lactase throughout their lives, but 25% of Americans and 75% of persons worldwide have lactase levels low enough to produce symptoms of lactose intolerance.

Lactose Intolerance Was Not Absolute

Suarez FL, Savaiano DA, Levitt MD. A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance. N Engl J Med. 1995; 333:1-4.

Large doses of lactose, such as the 50 g contained in a liter of milk, may cause diarrhea, bloating, and flatulence in most patients with lactose intolerance. It is unclear, however, whether smaller doses of lactose (for example, 12 g in 240 mL of milk) cause similar symptoms.

Suarez and colleagues evaluated symptoms in a self-selected group of 30 patients who reported that symptoms consistently occurred after they ingested as much as 240 mL of milk. The ability to digest lactose was first determined by measurement of breath hydrogen levels after ingestion of 15 g of lactose in 250 mL of water. In a randomized, double-blind, cross-over trial, participants received 240 mL of lactose-hydrolyzed milk (2% fat) or 240 mL of milk (2% fat and sweetened with aspartame to approximate the taste of lactose-hydrolyzed milk). Twenty-one participants were classified as lactose malabsorbers, and 9 were classified as normal lactose absorbers.

When the two trial periods were compared, symptoms were minimal and severity of symptoms (bloating, abdominal pain, diarrhea, and flatulence) among the lactose malabsorbers did not significantly differ. Suarez and colleagues concluded that when lactose intake is limited to 240 mL of milk per day, gastrointestinal symptoms are likely to be negligible in patients who have identified themselves as severely lactose intolerant.

These findings suggest that various abdominal symptoms are frequently misattributed to lactose intolerance. Further, the use of lactose digestive aids may be unnecessary for daily intake of 8 ounces of milk or less.

Aspirin and Colorectal Cancer

Earlier studies in men support the concept that regular use of aspirin and other nonsteroidal antiinflammatory drugs reduces the risk for colorectal cancer.

Aspirin Use Was Associated with Less Cancer in Women

Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC, et al. Aspirin and the risk of colorectal cancer in women. N Engl J Med. 1995; 333:609-14.

Giovannucci and colleagues sought to determine the rates of colorectal cancer in 89 446 participants in the Nurses' Health Study who completed detailed questionnaires on medication use. From 1984 to 1992, 331 new cases of colorectal cancer were documented during 551 651 person-years of follow-up.

The study findings are shown in Table 3. The age-adjusted relative risk for developing colon cancer decreased to 0.7 after 10 years of aspirin use and to 0.56 after 20 years of aspirin use. Although the benefit is not statistically significant until 20 years, the trend toward benefit is consistent across the duration of aspirin use. These results provide strong evidence that the risk for colorectal cancer in women is reduced with regular aspirin use. Furthermore, the amount of aspirin taken was associated with the decrease in the rates of colorectal cancer. The maximum risk reduction was seen in women who took four to six aspirin tablets per week.

Ulcerative Colitis

Several drugs are now available for the treatment of ulcerative colitis and Crohn disease, including sulfasalazine; 5-amino salicylic acid analogues that can be given orally, by suppository, or as enema preparations; corticosteroids that can be given intravenously, orally, or as enema preparations; metronidazole; such immunosuppressive drugs as azathioprine and methotrexate; and cyclosporine.

Mesalamine Maintained Remission of Ulcerative Colitis

An oral preparation of mesalamine as long-term maintenance therapy for ulcerative colitis. A randomized, placebo-controlled trial. The Mesalamine Study Group. Ann Intern Med. 1996; 124:204-11.

Several trials have indicated that mesalamine, a 5-amino salicylic acid analogue, is effective in long-term maintenance therapy for ulcerative colitis. These investigators sought to determine the efficacy of a pH-sensitive polymer-coated oral formula of mesalamine compared with placebo in maintaining remission in patients with ulcerative colitis. A total of 264 patients with ulcerative colitis that had been in remission for at least 1 month were randomly assigned to receive placebo, low-dose mesalamine, or intermediate-dose mesalamine for 6 months. Proctosigmoidoscopy was done at 1, 3, and 6 months; abnormal results indicated relapse.

The study findings are shown in Table 4. The data indicate that mesalamine in dosages of 0.8 g/d or 1.6 g/d safely and effectively maintains remission in patients with quiescent ulcerative colitis.

Gallstones and Weight Loss

Previous studies have shown that gallstones develop in 10% to 25% of persons who rapidly lose weight through very-low-calorie dieting. Ursodeoxycholic acid is a bile salt that reduces cholesterol secretion in bile, improves solubility of biliary cholesterol, and dissolves small, cholesterol-rich gallstones.

Ursodeoxycholic Acid Prevented Gallstones

Shiffman ML, Kaplan GD, Brinkman-Kaplan V, Vickers FF. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med. 1995; 122:899-905.

Shiffman and colleagues sought to determine whether prophylaxis with ursodeoxycholic acid could prevent gallstones in persons participating in a rigid weight reduction program. A total of 788 patients who were enrolled in and completed a 16-week, 520-kcal/d diet program were randomly assigned to one of four treatment groups: placebo or ursodeoxycholic acid at dosages of 300 mg/d, 600 mg/d, or 1200 mg/d. All patients had normal findings on gallbladder ultrasonography before starting the program. Ultrasonography was repeated after 8 and 16 weeks of dieting.

The study results indicate that ursodeoxycholic acid at a dosage of 600 mg/d prevents gallstone formation in patients participating in a very-low-calorie weight reduction program (Table 5).

Antibiotics and Pancreatitis

It had been suggested that antibiotic use offers benefit in acute pancreatitis, but no controlled trial had shown efficacy. The rate of death from pancreatitis has decreased, presumably because of improvements in critical and operative care. Still, infectious complications remain a major cause of death; most cases of sepsis are caused by Escherichia coli and Staphylococcus aureus.

Early Antibiotic Therapy Was Associated with Fewer Deaths

Sainio V, Kemppainen E, Puolakkainen P, Taavitsainen M, Kivisaari L, Valtonen V, et al. Early antibiotic treatment in acute necrotising pancreatitis. Lancet. 1995; 346:663-7.

In a randomized study of patients with acute alcohol-induced necrotizing pancreatitis, Sainio and colleagues determined whether outcomes could be improved by cefuroxime treatment started soon after hospital admission. Of 820 patients with acute pancreatitis who were admitted during a 4-year period, 60 consecutive patients with severe necrotizing pancreatitis were randomly assigned to one of two treatment groups. The antibiotic group received cefuroxime therapy (4.5 mg/d intravenously) that was continued until clinical recovery. The primary end point was survival.

The following is a summary of the study findings: Eight of 30 patients not receiving antibiotics and 4 of 30 patients receiving cefuroxime had sepsis; 12 and 8 patients, respectively, developed an abscess from infected necrosis; 14 and 7 patients, respectively, had surgery; and 2 and 0 patients, respectively, had fulminant pancreatitis with shock. Seven patients not receiving antibiotics and 1 patient receiving cefuroxime died. The total number of deaths, the number of patients who had surgery, and the number of episodes of sepsis that was blood-culture positive were all reduced in the group receiving cefuroxime. The striking finding is the decrease in the mortality rate in patients receiving antibiotics. Sainio and colleagues conclude that cefuroxime given for necrotizing pancreatitis may reduce mortality by decreasing the frequency of sepsis.

Dr. Roberts (Series Editor): York Health System Medical Group, York, PA 17313.