Monday, March 27, 2006
The Ulcer Giver: Helicobacter Pylori
By Dr. Shiban Ganju
Shiban is the chairman of a biotechnology company in India and a practicing gastroenterologist in the USA. He travels between these two spaces frequently but lives in them simultaneously. He has been a passionate theater worker, reluctant army officer, ambitious entrepreneur, successful CEO and an active NGO volunteer. Still, he is does not know what he wants to be when he grows up; but he wants his epitaph to be “He tried.”
A diminutive microbe, Helicobacter Pylori (HP) emerged from obscurity over twenty years ago and squirmed itself into fame and stardom! Since its stomach damaging felony was discovered, it has been accused of causing injury to other precious organs like heart and colon. The scientist sleuths are collecting evidence to indict it; the verdict is not yet in but it is likely that HP will be found guilty on some counts and exonerated of others.
This miniscule, (3 micrometers long), corkscrew like microbe eluded the scientists with diversionary tactics worthy of a hardened felon. HP created the trail of hyper acidity as the cause of ulcer disease and scientists spent decades to unravel the mystery of acid production.
The dogma in ulcer disease stated: stress increases Hydrochloric acid production which in turn erodes the duodenal or gastric (stomach) lining causing an ulcer crater.
Investigators found excessive acid and pepsin production in the stomach of patients with ulcer disease. Other associated culprits -- cigarettes, anti inflammatory drugs like aspirin and ibuprofen -- shared the blame.
Natural consequence was a multi million dollar business of acid neutralizing and suppressing drugs. Shelf loads of antacids and histamine-2 receptor blockers like Cimetidine (Tagamet) became the standard therapy. Later, the proton pump inhibitors like Omeprazole (Prilosec) and its variants entered the fray to abolish gastric acid.
When medical therapy failed, surgeons wielded their knives, especially for those patients with complications of bleeding, obstructed stomach outlets and indolent ulcers. Surgery involved cutting part of the ulcerated stomach or duodenum and reconnecting the stomach to the jejunum. Prominent surgeon Billroth attained immortality by naming one such procedure after him, only to announce a newer and improved version later that he named Billroth II.
Other surgeons innovated the cutting of the vagus nerve to abolish the stimulus to acid production. But it led to decreased motility of the stomach and stagnation of food, so other surgeons offered a solution by enlarging the gastric outlet opening into the duodenum (pyloroplasty).
So the dogma went on. Books, papers, seminars were devoted to discuss the virtues of one procedure and vices of the other. Newer acid suppressants proliferated and a few generations of gastric surgeons thrived. Meanwhile, some patients improved while others suffered more.
The beginning of the end of this mindset came with the discovery in 1983 by Barry Marshal and Robin Warren from Perth, Australia that the cause of gastritis and duodenal ulcer is this cork screw shaped bacterium Helicobacter Pylori. (Campylobacter pyloridis initially) Though this bacterium was found in the stomach lining by many investigators from 1875, it was Marshall and Warren who cultured these bacteria and found them in over 90 percent of duodenal ulcers. Marshall further nailed the etiology by satisfying Koch’s postulates. Koch, a renowned scientist, had suggested earlier that in order to validate an infectious etiology of a disease the following criteria had to be met:
- The organism is always associated with disease.
- The organism will cause disease in a healthy subject.
- Eradication of the organism will cure the disease.
- Re-challenge with the organism will cause the disease again.
Barry Marshall swallowed a Petri dish culture of H. Pylori and suffered severe gastritis; he recovered when the bacteria were eradicated and he did not re-challenge.
He satisfied three of the four postulates. After initial skepticism, as befits a dogma, other workers from all over the world replicated these findings. Suddenly ulcers of the stomach and duodenum were cured by simple antibiotic therapy for two weeks. Drs. Marshall and Warren won the Nobel Prize in 1995.
HP turns to be more interesting than a mere ulcer causing nuisance. It has four to six flagella at one end with which it penetrates the mucous layer and approach the gastric wall. The bacterium produces many enzymes including urease which breaks down urea into ammonia and bicarbonate which neutralize the surrounding acid creating a neutral pH cocoon around the bacterium. With glue like surface adhesins, HP clings to the gastric cells. Its secreted enzymes provoke the gastric G cells and D cells which enhance the Hydrochloric acid and pepsin production. An inflammatory response ensues and the lining succumbs to the onslaught of abrasive acid and inflammation. The surface breaks down and forms an ulcer. (Remember how research had shown increased acid production in ulcer patients: the cause was the bug and not stress!)
Investigators have shown that HP is present six times more often with gastric cancer and mucous associated lymphoid tumors (MALT) than in normal stomachs. Eradication of the infection with antibiotics clears the lymphoid tumors. (Here is a stunning example of antibiotics curing cancer!)
HP lives preferentially in the lower part of the stomach and passes in the faeces.The interpersonal transmission, therefore, is presumed to be fecal-oral. Over 50 percent of adults in the developed world carry this bug; the prevalence is higher in the developing countries. The prevalence increases with age.
The microbe is transmitted with in the family and travels with the family; this attribute has been used to study recent migration of human populations. The following example illustrates the point: the Ladakh region occupies northern tip of India and borders Tibet on the east and Kashmir on the west. The population of this region descends from Tibetan and Indo-Iranian stock. While genetically the two populations do not differ, the genomics of H pylori in their stomachs betray their migrations from their respective ancestral lands of Tibet and northwest India.
HP has reminded us again: 1. Microbes rule. 2. “Scientific” dogma can stupefy the mind 3.The dogma may even harm the very patients that are supposed to benefit from such knowledge.
What is the future of this bacterium? All bad things must come to an end! A mathematical model from Stanford suggests that H pylori will be extinct in one hundred years, at least in the USA. Its fifteen minutes of fame will be over.
Helicobacter Pylori, the diminutive flagellate, dispeller of dogma, generator of insight into cancer, tracer of human dislocations gives me “ulcers”, when, as a physician, I encounter patients with surgically mutilated stomachs from a bygone era. I shudder to think that the current “state of the art” in medical practice will be found similarly inadequate in future.
I pray we do no harm in the meantime.
Posted by S. Abbas Raza at 12:05 AM | Permalink
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