Basil I. Hirschowitz, MD
Professor Emeritus
Department of Medicine, Division of Gastroenterology
The University of Alabama at Birmingham
Birmingham, Alabama

In accordance with the Accreditation Council for Continuing Medical Education Standards for Commercial Support, Dr. Hirschowitz discloses grants and research support from TAP Pharmaceuticals and he is a consultant for TAP Pharmaceuticals.

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Proton-pump inhibitors (PPI), the best selling drugs in the world today, are largely used for treatment of symptoms and disease due to gastroesophageal reflux and peptic ulcers and as prophylaxis in persons taking ulcerogenic medications. The National Institute of Diabetes and Digestive and Kidney Diseases estimates more than 14 million Americans live with peptic ulcer disease, which for decades was attributed to stress and lifestyle issues.

Australian researchers Barry J. Marshall, MD, and J. Robin Warren, MD, challenged prevailing dogma related to cause of peptic ulcer disease and found the spiral-shaped bacterium Helicobacter pylori causes the majority of peptic ulcers (duodenal or gastric). The pair received the 2005 Nobel Prize in Physiology or Medicine for their discovery of H pylori and its role in gastritis and peptic ulcer disease.

“Ulcers caused by H pylori can be treated with new 7- to 10-day combinations of PPIs and antibiotics, which eradicate most H pylori, thereby permanently curing ulcers caused by the bacteria. What remains are a proportion of peptic ulcers not related to H pylori, esophageal reflux, and hypersecretion issues that must be treated with appropriate medical therapies,” explains UAB gastroenterologist Basil I. Hirschowitz, MD.

Hirschowitz is recognized internationally for his invention of an improved optical glass fiber and the development of the flexible endoscope, which modernized gastroenterologic diagnostic and treatment techniques and which he continues to refine today.

Peptic Ulcers of Nonbacterial Origin

Between 20% and 30% of peptic ulcers are not caused by H pylori, Hirschowitz says. Common symptoms are dyspepsia, including epigastric pain, nausea, and vomiting.

Independent of H pylori, nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, are the second most common cause of peptic ulcers, although patients may misrepresent or not fully understand their NSAID intake. A 2002 UAB study found nearly 7% of 1845 peptic ulcers were due to NSAIDs or aspirin and resistant to treatment. Aspirin abuse was identified by evidence from elevated serum salicylate levels, even though many patients denied aspirin use (Jour Clin Gastro. 2002;34:523-528).

“Many did not understand they were taking aspirin, which is found in numerous common over-the-counter medications, such as Stanback headache powders and Alka Seltzer,” Hirschowitz says.

“Aspirin-abuse ulcers differ from the usual H pylori peptic ulcers and from those due to acid hypersecretion or a gastrin-producing pancreatic tumor called a gastrinoma,” explains Hirschowitz, the study’s lead author. “Aspirin-abuse ulcers present atypically, often in multiple locations, and with many complications. Bleeding, pyloric or duodenal stenosis, esophageal strictures, and perforations are more common in peptic ulcers related to aspirin than in peptic ulcers due to other causes. Unless aspirin abuse is stopped, these ulcers remain incurable and extremely dangerous.”

Abnormal reflux of gastric contents into the esophagus causes heartburn, the telltale symptom of gastroesophageal reflux. Reflux affects more than 60 million Americans at least once a month and is an everyday problem for about 25 million. Reflux of gastric contents can result in mucosal damage (esophagitis) with esophageal erosion or ulceration and further complications, such as stricture or Barrett esophagus, collectively defined as gastroesophageal reflux disease (GERD).

Gastroesophageal reflux is usually due to lower esophageal sphincter incompetence, abnormal transient lower esophageal sphincter relaxation, or hiatal hernia. Gradually, acid, pepsin, trypsin, or bile acids overcome esophageal acid clearance and mucosal resistance, leading to esophagitis.

“Endoscopy demonstrating esophagitis or Barrett esophagus [a possible predictor of esophageal adenocarcinoma] confirms gastroesophageal reflux, yet many symptomatic patients present with normal endoscopy, so-called nonerosive reflux disease. Whether esophagitis is present or not, patients with gastroesophageal reflux symptoms have pathologic amounts of acid reflux that are best controlled with a PPI,” he advises.

In its most recent gastroesophageal reflux guidelines, the American College of Gastroenterology advised offering empirical treatment for patients with reflux-consistent symptoms, ie, heartburn, and to reasonably assume the diagnosis of reflux in patients responsive to appropriate therapy. However, in reflux patients, physicians should further evaluate alarm symptoms, such as chronic undiagnosed cough, hoarseness, or both, difficulty swallowing, bleeding, anemia, or weight loss by endoscopy or barium swallow (Available at: www.acg.gi.org/physicians/guidelines/GERDTreatment.pdf. Accessed March 14, 2006).

A further subset of ulcers not due to H pylori or NSAIDs, comprising about 10% of duodenal ulcers, are caused by excessive acid production due to an overactive vagus nerve. “Resembling Zollinger-Ellison syndrome, these ulcers are not caused by a gastrinoma,” Hirschowitz says.

Excessive acid secretion in Zollinger- Ellison syndrome, an uncommon condition, is caused by gastrin-secreting tumors, which are often multiple, usually located in or near the pancreas, and sometimes metastasize to regional lymph nodes and occasionally beyond, Hirschowitz says. Acid hypersecretion from elevated gastrin causes continuous high rates of acid secretion, leading to severe ulcer disease, esophagitis, diarrhea, and frequent complications such as bleeding or perforation.

“Because gastrinomas are uncommon, they are often misdiagnosed. Additionally, they can present with conventional symptoms of peptic ulcers,” he notes. However, patients with underlying gastrinomas may have multiple and rapidly recurrent ulcers. These ulcers are not related to H pylori or NSAIDs. Persistent peptic ulcers with esophagitis and unexplained diarrhea or hypercalcemia, excessive vomiting, or weight loss may be clues to the diagnosis of Zollinger-Ellison syndrome.

“If the diagnosis is suspected, elevated serum gastrin and very high gastric acid secretion indicate Zollinger-Ellison. Zollinger-Ellison ulcers usually respond to treatment, but relapse rapidly. PPIs are the preferred and essential treatment, suppressing acid to normal or low levels and thereby controlling the disease indefinitely. Patients must be carefully and consistently monitored for recurrent disease,” he says. “In the long term, surgery to remove a gastrinoma is successful in no more than 10% to 20% of cases and should be offered to patients rarely, and then only after intensive and specialized tests.”

Gastrinomas occur with equal frequency among men and women, yet duodenal ulcers with hyperacid secretion not due to gastrinomas occur almost exclusively in men, UAB studies report. An ongoing, 17-year prospective study examined more than 80 acid hypersecreting patients (including 60 with Zollinger-Ellison syndrome) taking individually optimized doses of lansoprazole. Hirschowitz and colleagues found an overwhelming majority of patients with optimal medical suppression of acid had good or excellent long-term outcomes without surgery, with relapse rates lower than 5% (Clin Gastroenterol Hepatol. 2005;3:39-48).

Before treatment, 94% of participants had duodenal ulcers, 64% had esophagitis, 60% had one or more bleeding episodes, 13% had perforated ulcers, 90% had pain, 60% had heartburn, and about 40% had diarrhea, vomiting, weight loss, or all three. “Overall, treatment reduced symptoms and disease manifestations, including bleeding and perforation, by 90% or more,” he says. “Interestingly, in patients with Zollinger-Ellison syndrome, the stomach is immune to excess acid production. Gastric ulcers are more common in people affected by H pylori or NSAID use but extremely rare with Zollinger-Ellison.”

In acid hypersecretion and severe esophagitis, serum gastrin levels and gastric analysis measuring the output of stomach acid provide important information about diagnosis and management. “Gastric analysis provides specific benchmarks [15 mEq/h] for diagnosing Zollinger-Ellison and less than 5 mEq/hr for optimizing PPI dosage,” Hirschowitz says. “Since high gastrin levels occur with both gastrinomas and nonacid producing pernicious anemia, empiric analysis [high vs 0] of acid output is critical to proper diagnosis.”

Endoscopy is essential for diagnosis of upper gastrointestinal diseases including esophagitis, pain, and bleeding. In some cases, treatment, especially for heartburn and GERD, can precede diagnosis, he says. “Some patients, especially those with infrequent heartburn, should be treated first, with endoscopy reserved for those whose symptoms are not controlled with medications or who have alarm symptoms such as dysphagia, odynophagia, or weight loss. Esophagogastroduodenoscopy can be used for biopsy of Barrett esophagus every 1 to 3 years, depending on whether atypia is present on biopsy.”

Persistent symptoms of peptic ulcer disease require an endoscopy for accurate diagnosis of location, size, signs of bleeding, pH measurements of gastric contents, and H pylori, which is also diagnosable by nonendoscopic means, he says. “Serial endoscopy for ulcers, which are adequately cured in nearly all patients, is not indicated, except perhaps for those with persistent symptoms that may have a different cause, such as NSAIDs, bleeding, or Barrett esophagus.”

Interventional endoscopy is used for control of bleeding, removal of polyps, superficial cancers, and esophageal or pyloric strictures.

With Hirschowitz at the helm of ulcer studies, UAB has been at the forefront of decades of research on drugs to suppress acid secretion. “Prior to the 1974 development of histamine H2-receptor antagonists, for which British pharmacologist James Black earned the Nobel Prize, the only available drugs for treating acid disorders were belladonna [atropine] and antacids, and clinicians relied heavily on surgery. Modern H2 antagonists dramatically changed treatment. UAB has conducted extensive research and testing on antagonists such as cimetidine [Tagamet] and ranitidine [Zantac] to control acid disorders,” he says.

In the early 1980s, PPIs were developed as potent acid inhibitors. “Specifically, they intervene in the final proton-pump or acid-pump pathway [H+-K+-ATPase], shutting off acid output and functioning as ideal medicines for treating acid-related ulceration and esophageal reflux,” he says.

The more potent PPIs have largely replaced H2-receptor antagonists for long-term control of acid-related diseases. PPIs have a well-established safety profile, although some questions remain about potential side effects over long periods. “Rat studies indicating long-term acid suppression could lead to gastric carcinoid development prompted a temporary delay in Food and Drug Administration approval of PPIs in the 1980s. However, more than 300 million people have taken these drugs, and human cancer risks have failed to materialize,” Hirschowitz says.

“Yet, lifelong treatment with PPI drugs is not for everyone, he says. “Not all patients are equally responsive to the medicines, but optimizing treatment regimens based on gastric analysis significantly improves outcomes. In the 20th century, eradicating H pylori and targeting individualized treatments revolutionized management of acid disorders,” he concludes.

For more information:

Dr. Basil Hirschowitz
1-800-UAB-MIST
mist@uabmc.edu

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