25 Years in Peptic Ulcers: From Chronic to Curable

Dec. 25, 2009— -- In 1984, 33-year-old Barry Marshall, frustrated by responses to his work, ingested Helicobacter pylori, and soon developed stomach pain, nausea, and vomiting -- all signs of the gastritis he had intended to induce.

"I didn't actually expect to become as ill as I did," he wrote in an autobiography about one of the defining moments of his research, which ultimately led to winning the 2005 Nobel Prize with his now-retired colleague, Robin Warren.

The event followed the publication of two papers in The Lancet in 1983 and 1984. In those articles, Warren and Marshall, now at the University of Western Australia in Perth, described an association between a new bacterium that would eventually be named H. pylori and peptic ulcers, both duodenal and gastric.

Warren and Marshall had become convinced that the bacteria, successfully cultured after being left out inadvertently over a long holiday weekend, were causing the ulcers. But Marshall had met stiff resistance from gastroenterologists around the world when he broached the idea.

Conventional thinking at the time was that ulcers were caused by excess acid in the stomach and that no living organism could live in such an acidic environment. As it turns out, H. pylori produces ammonia to neutralize the area around it.

Dr. Walter Peterson, now a clinical professor at the University of Colorado Denver, was a member of the skeptical majority. He said Marshall called him and his colleagues the "Acid Mafia."

"Barry Marshall came across as a zealot, as opposed to a scientist," he told MedPage Today, describing Marshall as a good friend now.

Marshall wrote in his Nobel Prize autobiography, "I was met with constant criticism that my conclusions were premature and not well supported. When the work was presented, my results were disputed and disbelieved, not on the basis of science but because they simply could not be true."

But a conviction that he was right and a sense of urgency surrounding the importance of reducing the burden of ulcers -- which affected about 10 percent of Americans at some point in life -- led him to famously use himself as an animal model.

"If I was right, then treatment for ulcer disease would be revolutionized. It would be simple, cheap, and it would be a cure," he wrote, using a word often considered taboo when discussing medical research.

After fighting through years of ridicule, Marshall's overzealousness paid off.

"We were wrong, he was right," Peterson said. "And so I couldn't agree more that he got the Nobel Prize."

It's now well established that H. pylori is a major cause of peptic ulcers, with use of non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, indomethacin, and the non-selective COX inhibitors footing some of the blame.

"Nowadays, we know that most ulcers are caused by disruption in mucosal defense and not by excess acid," Peterson said.

Warren and Marshall's discovery revolutionized the management of peptic ulcer disease, which had been a chronic condition requiring continuous use of medications believed to be induced by poor diet and stress.

In the early 1980s, patients presenting with stomach pain would undergo endoscopy or X-ray to look for an ulcer. When one was found, patients would be treated with agents to lower the levels of stomach acids -- antacids into the late 1970s followed by histamine2 receptor antagonists. More potent proton pump inhibitors wouldn't arrive until the U.S. Food and Drug Administration approved omeprazole (Prilosec) in 1989.

Ulcers would heal, but ultimately return.

"We could control the ulcer, but not cure the ulcer," Peterson said.

According to Dr. David Graham of Baylor College of Medicine in Houston, "It was a bad existence. [It was] very expensive, you had to frequently go to doctors and you had lots of X-ray examinations, or later, endoscopic examinations to show if an ulcer was present or not."

Serious complications, such as gastrointestinal hemorrhage, strictures, and perforations, occurred in about 25 percent of patients, many requiring surgery. About 10 percent of those died, Graham said.

Like Peterson, Graham doubted Warren and Marshall's findings.

"Dr. Marshall, when he first presented this, was young, a resident, and didn't know how the system worked," Graham said in an interview. "And he believed that just because you could show people and it all made sense that they would believe it. But you just need to do the studies to get the proof and show that if you eradicate the infection that the ulcer disease is also cured, and that takes time."

Studies did confirm the causal role of H. pylori, and Graham and Peterson eventually accepted the idea. They both became leading U.S. experts studying the bacteria and how to treat it.

Peterson couldn't identify a tipping point for when acceptance of a causal role for H. pylori started to gain traction. He said it came after researchers from around the world started to confirm the Australians' findings and show that treating the infection cured the ulcers.

Graham said official acceptance of the idea came at a 1994 National Institutes of Health consensus conference that concluded that there was a strong link between H. pylori and peptic ulcer disease -- and that patients with ulcers and infection with the bacteria required treatment with antibiotics and antisecretory drugs.

"I had been waiting for 10 years for this day, and I felt a combination of relief and satisfaction that I had achieved what I set out to do," Marshall wrote.

But still, clinicians were slow to accept H. pylori.

In a 1997 study in Archives of Internal Medicine, researchers found that, in 1995, about three-quarters of ulcers were still being treated primarily with antisecretory medications. Only 5 percent of patients received antibiotics.

It wasn't until 1996 that the FDA approved the first antimicrobial treatment for peptic ulcers -- a combination of the antibiotic clarithromycin (Biaxin) and the proton pump inhibitor omeprazole.

In 1997, responding to the clinical inertia preventing the widespread use of antibiotics to treat ulcer disease, the CDC launched a national campaign to spread the word through public service announcements on television and radio.

Around the end of the 20th century, Graham said, the idea finally took hold.

This process "probably happened slower than it should have, but about as fast as new ideas travel through medicine."

Now, the proportion of ulcers attributed to H. pylori is declining, although it varies depending on location.

Graham said that at his center in Houston about half of new ulcers are caused by H. pylori, with the rest caused by NSAIDs.

Peterson said that at a university hospital, like his in Denver, almost no ulcers are caused by H. pylori.

Ulcers caused by the bacteria are more frequent at centers caring for more socioeconomically disadvantaged populations.

Graham said that the prevalence of H. pylori was on the decline even before gastroenterologists started treating ulcers with antibiotics because of its fecal-oral transmission route.

It's a disease of poor hygiene and poor sanitation, he said, and doesn't transmit well between people. Quality sanitation had the bacteria retreating already in developed countries, although H. pylori remains a major problem in the developing world.

In the U.S., management of patients with ulcers involves testing for the bacteria. This can be done on biopsies taken during endoscopy, or with less-invasive blood, fecal antigen, and urea breath tests.

The "test-and-treat" approach says that if a patient shows signs of an ulcer and is positive for H. pylori they can be treated to eliminate the infection, without the need for endoscopic confirmation of an ulcer.

"The theory being that if they actually had an ulcer by treating H. pylori we would get rid of the ulcer, and if they didn't then that's okay. Getting rid of H. pylori was probably good in and of itself," Peterson said.

According to the most recent guidelines from the American College of Gastroenterology, published in 2007, first-line treatments for H. pylori ulcers include 10 to 14 days of therapy with a proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole or a proton pump inhibitor, bismuth, tetracycline, and metronidazole.

Graham noted that there is increasing resistance to clarithromycin, which is not well known by clinicians. He said that H. pylori is sensitive to many other antibiotics.

In patients who show signs of an ulcer but who are H. pylori-negative, endoscopy is required to confirm an ulcer.

If it's determined that a patient has been taking an NSAID, stopping the drug and starting on antisecretory therapy will heal most ulcers, according to Graham. Healing time varies based on the severity of the ulcer, with some of the deepest ones taking six or seven months to heal completely.

But unlike in the past, "virtually every ulcer that we see is ultimately healed," Peterson said.

As perhaps a sign of the importance of Warren and Marshall's discovery, Graham said he was recently asked to condense five chapters on peptic ulcer disease in a major medical textbook into one.

"Peptic ulcer disease has become a minor event and eventually will become historical as far as a concept," Graham said.