Course Authors

Gary M. Gray, M.D.

Dr. Gray reports no commercial conflict of interest.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 0.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

 

Peptic diseases include erosions and ulcers that develop in the duodenum, stomach and lower esophagus in response to the presence of acid and the protease, pepsin. In recent years, it has been documented that the use of non-steroidal anti-inflammatory drugs (NSAID's), e.g., aspirin, naproxen, ibuprofen or indomthacin, or infestation of the stomach with Helicobacter pylori reduces mucosal resistance and sets the stage for peptic ulcerations. Even though the prevalence of peptic disease has been declining in the United States over the last 40 years, it still is relatively common, especially in patients who are chronically ill with diseases of other systems.

The advent of more precise diagnostic modalities such as upper gastrointestinal fiberoptic endoscopy has made it possible to document the presence of mucosal friability, active erosions and ulcerations that could not be reliably identified by barium contrast X-rays. Also, endoscopy has verified an appreciable discrepancy between symptoms and the extent of the ulcerative disease. We now know that patients under major stress of a systemic disease may have extensive peptic lesions and complications such as bleeding or obstruction in the absence of typical symptoms of epigastric pain or heartburn that are relieved by food.

Peptic Disease Alerts Us to Two Underlying Causes

When considering peptic disease, think of NSAID's and H. pylori. Because the stage is set either by substantial use of NSAID's or by H. pylori (HP) gastric infestation in most individuals with peptic disease, it is important to assess the role of these two factors in patients with peptic symptoms. An accurate history of non- steroidal drug usage is often very difficult to obtain. The physician should review a list of NSAID's with the patient that may have been taken for chronic headaches or joint stiffness and pain. Not infrequently, patients deny they are taking pain-relieving drugs until extensive pre-pyloric and duodenal ulcerative disease prompts the physician to address more thoroughly the question of NSAID use.

In about 40% of healthy persons in the world's adult population and in two-thirds of those with recurrent peptic ulcer disease, HP grows in the overlying mucus of the stomach antrum; while the organism does not penetrate the gastric cell, it changes the composition of mucus and appears to hamper the mucosal barrier against the acid and pepsin, resulting in antral gastritis. Though HP does not grow in the duodenal bulb, patients who harbor the organism in the gastric mucus have a relatively high prevalence of duodenal ulcer and eradication of HP reduces dramatically the risk of recurrence of peptic disease.

Diagnostic Steps in Peptic Disease

Besides the typical symptoms of epigastric discomfort or heartburn relieved by ingestion of food, patients with new onset peptic disease will often note hunger pangs between meals and may gain weight as a consequence of increased caloric intake.

Evaluation in the Younger Patient (< Age 40)

Although some experts recommend upper gastrointestinal endoscopy for persons of any age who present with abdominal pain, a reasonable initial approach to diagnosis in patients with typical peptic symptoms who are under age 40 is the meticulous documentation of any NSAID usage, discontinuation of all NSAID drugs, and a diagnostic-therapeutic trial of an appropriate acid-lowering agent (see below and Tables 1,2).

If the patient experiences typical recurrent symptoms within six months, an upper gastrointestinal endocopy should be performed to verify the nature of the epigastric symptoms and to assess the status of HP infestation by the urease test of an antral biopsy.

Evaluation in the Middle-Age and Older Patient

For patients with suspected peptic disease who are age 40 years or older, assessment of the upper gastrointestinal tract should be accomplished at the outset because of the higher risk of more serious disease such as carcinoma or lymphoma in the older patient. Although an upper gastrointestinal barium contrast X-ray series can be the initial diagnostic study, an esophagogastroduodenoscopy is recommended in most middle- aged patients because of its greater sensitivity in identifying an early neoplastic lesion. Any subtle abnormality observed at endoscopy can be readily biopsied under direct vision.

When endoscopy is performed in a patient with suspected peptic disease, the finding of mottling with ~1 mm in diameter flat red-colored lesions in the distal stomach is usually indicative of gastritis. Patients with these findings or with more advanced lesions such as friability (ready bleeding when the tip of the endoscope is brushed against mucosa), erosions or ulcerations should have biopsies taken for HP analysis. The presence of HP can be documented accurately by testing of antral biopsy material obtained at endoscopy for a) urease assay (CLO test) and b) special histological Warthin-Starry staining.

In addition, when upper gastrointestinal endoscopy is not warranted, the serum antibody titer against the organism may be useful in verifying exposure to the organism. Although the urease assay and histological staining are considered to have the greatest sensitivity and specificity for identifying the HP infestation, non- invasive tests such as the [14C]urea or [13C]urea breath tests(1) that reflect the metabolism and excretion of urea and the IgG serology test for the HP antigen appear to approach the accuracy of the tissue analyses, particularly when the latex agglutination technique is used.(2)

Advances in Acid Lowering: From Acid Neutralizers to Secretory Blockers

Therapy has evolved from the alkali antacids, used over the years to relieve peptic pain but not believed to augment ulcer healing, to the demonstration that relatively low-dose aluminum-magnesium hydroxide or calcium carbonate antacids (40 mMoles 2hr. p.c. and h.s.) will accelerate healing of peptic ulcers by about 50 % over four to six weeks.(4)

As potent blockers of histamine-stimulated acid secretion, the histamine type-2 receptor antagonists (H2-RA's) are comparable to antacids in augmenting ulcer healing and their availability in the form of small tablets has made them readily acceptable to patients (see refs. 7-10 for utility of the particular H2-RA's).

More recently, direct inhibitors of the gastric hydrogen ion secretory mechanism, the proton pump inhibitors (PPIs), omerazole and lansoprazole, have been shown to be exceptionally fine inhibitors of acid secretion.(11),(12) This has made them particularly useful in the therapy of severe erosive esophagitis. Anticholinergic agents have not been used as frequently in recent years because of prominent side-effects such as dry mucous membranes and difficulty with accomodation of vision, but a gastrointestinal selective anticholinergic, pirenzepine, is promising and may soon be approved by the FDA for use in suppression of acid secretion.(13)

Recent guidelines for therapy of peptic ulcers have been brought forth with the approval of three major gastroenterology associations.(14) These can be summarized as three general recommendations:

• A peptic ulcer found in association with gastric infestation with H. pylori warrants both acid-lowering agents and combined antibiotic therapy to heal the ulcer and eradicate the organism.
• If ulcers fail to heal over the usual course of acid-lowering therapy, maximal inhibition of acid should be instituted and the eradication of the H. pylori should be verified.
• In patients who develop gastric or duodenal ulcers while taking NSAID's, the offending drug should be discontinued and the possible contribution of H. pylori should be evaluated.

But the Therapeutic Options are Broad. How does the Physician Choose?

With the myriad of drugs and therapies now available, the physician may become perplexed about the prospects of initiating therapy and maintaining treatment of recurrent disease.

Treatment: Cost-Effective Reduction of Gastric Acid

When a patient under age 40 presents with symptoms typical of a peptic diathesis (mild to moderately severe aching or burning sensations in the epigastrium with relief after food ingestion; increase in hunger sensations between meals; night wakening with epigastric discomfort), any NSAID usage should be discontinued and a treatment trial of an acid-lowering agent such as alkali antacids (40 mMoles 1 and 3 hrs p.c. and h.s.) or an H2- receptor antagonist (H2-RA; one tablet of the appropriate dose in the morning and at bedtime) is in order (see Tables 1 & 2 for names and dosages). Alternative therapy with the ulcer-coating drug sucralfate (Carafate®) is equally effective and is essentially free of side-effects, but more dosages (1 Gm q.i.d.) are needed than for the H2-RA's. For the rare patient who must take an NSAID for another disease, the prostaglandin analog, misoprostol (Cytotec®) 100-200 may be most effective in healing the NSAID- induced ulcers.(15) Diarrhea develops in 20-30 percent of patients who take misoprostol.

^a High potency antacids designated as Extra-Strength (ES or EX), Maximal Strength (MS), Plus or Double Strentgh (DS)

^b 40 mMole neutralizing capacity per dose, given q.i.d.

^c Prices in the San Francisco Peninsula, Dec. 1996.

Since many health care plans do not contribute to the cost for drug therapy, consideration must be given to the cost to the patient of peptic ulcer treatment (Tables 1 & 2). There has been about a 25 percent lowering of the non-prescription cost of the alkali antacids in the last two years, probably as a consequence of the availability of over-the-counter H2-RA's. Alkali antacids, while more cumbersome to take than the H2-RA's, cost only 32 to 67 cents per day (Table 1). The H2-RA therapy by prescription costs $2 to more than $3 per day for the appropriate twice daily dosage (Table 2). The cost of sucralfate or misoprostol is about $3 per day. The same dosage of an H2-RA can be achieved by use of two half-strength tablets twice daily, now available over-the-counter for about $1.33 per day at "discount" pharmacies. These can often be obtained at even lower cost (~$1 per day) if purchased in bulk quantities of 70 or more tablets.

^a Prices at Stanford outpatient pharmacy, Jan. 1997.

^b The lower price for Cimetidine is for the generic preparation; price in parenthesis are for the Tagamet proprietary form. Other H2-receptor antagonists are not available generically.

In the younger patient not requiring the initial upper G.I. endoscopy, the diagnosis of peptic disease is confirmed when dramatic relief of symptoms occurs within a few days. For acceleration of full ulcer healing, therapy should be continued for six weeks and the patient must be cautioned to complete the course of treatment despite the absence of continuing symptoms. If typical recurrent symptoms recur within six months after treatment, upper gastrointestinal endoscopy should be performed to verify the diagnosis and eliminate the possibility of HP infection, a large ulcer in the gastric body, carcinoma or lymphoma.

Treatment: Eradication of H. Pylori

If there is evidence of gastritis, typical peptic ulcers in the antrum, peri-pyloric area or duodenum, or a gastric ulcer in the body of the stomach, a biopsy for urease test (CLO test) and histologic analysis for HP should be performed. A positive test in any patient with peptic ulcer disease warrants treatment to eradicate the organism. Though many treatments have been advocated, none have been found to be ideal because of the cumbersome nature of the required multiple drug therapy.

The classical triple-therapy (bismuth subsalicylate, 2 tabs q.i.d.; metronidazole, 250 mg t.i.d.; and tetraclycline, 500 mg t.i.d. for 14 days) eradicates the organism in approximately 90 percent of patients with a gastric HP infection. But many patients object to the large dose of bismuth and the resulting darkened tongue and stools; also, resistance of the HP to metronidazole is not uncommon. If the patient has recently taken metronidazole for another condition or if there has been prior HP infection, the drug should not be included in the regimen. Early enthusiasm for the more palatable regimen of a proton pump inhibitor (PPI) such as omeprazole in combination with a single antibiotic has waned after the cure rates of only about 50 percent were achieved.(16)

General guidelines are now emerging for the therapy of this often stubborn gastric infection:

1. The classic triple-therapy can be prescribed for those patients who have not had recent therapy with metronidazole and who can tolerate the expected side-effects of bismuth (see above). But for an increasing proportion of patients, a potent acid-lowering agent, usually at twice the dose used for uncomplicated peptic disease, should be prescribed in combination with two antibiotics.(17)
2. High cure rates do not begin to occur until at least seven days of therapy(19) and a full 14 days of therapy is recommended.
3. The PPI's have been used most extensively and successfully as the acid-lowering agents in relatively high dosage. A twice daily regimen of a PPI (omeprazole, 20 mg b.i.d. or lansoprazole 30 mg b.i.d.) and two antibiotics such as amoxicillin (1000 mg b.i.d.) and clarithromycin (500 mg b.i.d.) is well tolerated and achieves eradication of the H. pylori in more than 90 percent of cases. I prefer double-dose PPI and dual antibiotics for most patients with peptic disease who are HP positive. After the two-week regimen, an acid-lowering agent alone should be continued for an additional month.

The Special Case of Peptic Esophagitis

Patients with hiatus hernia who have a patulous esophagogastric junction and poor lower esophageal sphincter tone are susceptible to esophageal reflux of gastric secretions. Commonly called gastrointestinal reflux disease or GERD, the regurgitation of acid often produces an erosive inflammation of the lower esophagus. Patients complain of severe heartburn, not infrequently progressing over weeks or months to the sensation of painful passage of solid foods (odynophagia). Over more prolonged periods, the chronic inflammation may lead to true dysphagia due to a stricture of the lower esophagus that often requires dilatation. In most patients with esophagitis, it is a chronic condition that produces appreciable symptoms over many years in about three-fourths of patients, half of whom experience heartburn daily and one-third of whom require daily drug therapy.(20) There is also the concomitant risk of alteration of the epithelium to a metaplastic columnar transitional type, called Barrett's epithelium, that has a propensity to become cancerous.(21)

Peptic esophagitis has been difficult to treat with the conventional acid-lowering alkali antacids or H2-RA's, but it is much more responsive to the PPI's.(22) Many patients who fail to respond to these drugs achieve a full remission with the usual minimal dosage of a PPI (omeprazole 20 mg/day or lansoprazole 30 mg/day), and half that dosage may be sufficient to alleviate symptoms completely and heal the esophagitis in many patients.(23) Some patients do require twice this dosage, and the addition of a prokinetic drug such as cisapride (Propulsid^®), 20 mg q.i.d., to augment esophageal and gastric motility may provide an incremental advantage for stubborn disease.(24) Although not yet approved by the FDA for long-term therapy of esophagitis, clinical studies have demonstrated the efficacy and safety of long term use of the PPI's in persistent GERD.(23)

Additional aspects of peptic diseases to be considered in upcoming conferences:

• Preventive Therapy in the Intensive Care Unit
• Barrett's Epithelium and Cancer in Esophagitis
• The Bleeding Ulcer