How Acid Suppression Raises the Cancer Risk

There is a paradox that baffled medicine early in the nineteenth century. That is when it was first noticed that people who have gastric ulcers tend to get stomach cancer, while those with duodenal ulcers do not. Once the role of H. pyloriinfection in duodenal and gastric ulcers and atrophic gastritis was discovered in the 1980s and 1990s, the paradox took on another dimension: H. pyloricould be the causative agent in either duodenal ulcers or gastric cancer, but hardly ever both at the same time. On the other hand, gastric ulcers and gastric cancer can occur simultaneously. The most recent confirmation of this paradox was a well-controlled U.S.-Swedish study that found twice the expected rate of gastric cancer in people who had gastric ulcers but 40 percent less than expected in those with duodenal ulcers (see Figure 1).
figure 1:The ulcer-cancer paradox. Having duodenal ulcers (and excess gastric HCI) appears to preclude gastric cancer, while having gastric ulcers (and an HCl deficiency) increases the risk. Adapted from L-E Hansson et al., 1996.
How can this be? The likely answer lies in—you guessed it—gastric pH. Remember we mentioned earlier that duodenal ulcers were associated with hyperacidity, while gastric ulcers occur in an environment of hypochlorhydria or achlorhydria. A low gastric pH (remember low pH = high acidity) is the normal state of affairs for the stomach and could not be carcinogenic, even if acid levels were excessive. (If that were the case, the human species would have died out eons ago. On the other hand, an elevated pH—an unnatural condition associated with disease (e.g., H. pylori infection, atrophic gastritis)—is an important risk factor for gastric carcinoma.
There appear to be at least two major mechanisms by which hypochlorhydria and achlorhydria elevate the risk of stomach cancer: by raising gastrin levels (hypergastrinemia), and by promoting bacterial overgrowth.

Hypergastrinemia Speeds Up Mucosal Cell Growth

Hypergastrinemia (high gastrin levels in the blood) typically occurs in people with atrophic gastritis or in those who take acid-blocking drugs for long periods of time. The amount of gastrin in play at any one time is a direct reflection of the current level of stomach acid. Low acid levels (pH 3 or higher) in gastric atrophy trigger higher gastrin levels as the stomach tries to compensate for the loss of acidity. A standard 20-mg daily dose of Prilosec causes up to a three- to four-fold increase in gastrin levels. In people whose heartburn/GERD fails to respond to the standard dose, long-term treatment with doses as high as 40 or 60 mg has produced gastrin levels as much as tenfold above normal.
Chronically elevated gastrin is a concern due primarily to its ability to raise the risk of developing stomach cancer. The hormone normally promotes the growth and proliferation of new histamine-secreting ECL cells as well as acid-producing parietal cells in the lining of the stomach. A steady supply of new ECL and parietal cells is required to replace those that succumb to the hostile gastric environment, especially in the fundus, where acid levels are highest. Thus, turning up the gastrin flow not only increases stomach acid, but it also speeds up the ECL cell assembly lines. As long as the increase in gastrin matches the decrease in acid, everything hums along normally. But when the gastrin supply badly exceeds the demand, ECL cell growth may be excessive. Known as hyperplasia, excess ECL cell growth is common in people with atrophic gastritis and has been observed in people taking Prilosec as well.
In some people, such growth can turn cancerous. This may be similar to the situation in women, where too much estrogen in the breast or uterus stimulates hyperplasia, which occasionally develops into cancer. There is currently no clear evidence that taking acid-suppressors for a long time directly causes stomach cancer. However, it is known that the risk increases in people with atrophic gastritis, which can take decades to develop fully. Few people have been using Prilosec or other even more powerful PPIs regularly for more than six or seven years, so far.
If rat studies are a lesson, though, long-term use of acid-suppressing drugs may indeed be risky. In one study, twenty-four months of use caused a statistically significant dose-related increase in ECL hyperplasia and gastric carcinoid tumors (known as ECLomas). When people take Prilosec for up to five years, examination has revealed a positive correlation between precancerous changes in the stomach lining and the degree of atrophic gastritis. No cases of stomach cancer have been attributed outright to the use of Prilosec or any other acid suppressor yet, however.
Carcinoid tumors are usually less serious than adenocarcinomas, but they can still be troublesome and extremely dangerous. This is because they flood the body with gastrin, which responds with a virtual flood of stomach acid. In the condition known as Zollinger-Ellison Syndrome (ZES), carcinoid-induced hypergastrinemia leads to extremely high gastric acid levels. All that acid eventually overpowers the stomach’s natural acid protections and leads to the formation of multiple severe ulcers, especially in the duodenum. ZES is one of the few conditions known in which stomach acid levels are actually too high.
Dramatic hypergastrinemia is also a key symptom of the disease known as pernicious anemia, which is associated with severe atrophic gastritis and malabsorption of vitamin B12, as well as both carcinoid tumors and gastric adenocarcinomas. In pernicious anemia, atrophic gastritis is so severe that parietal cells lose the ability to secrete not only acid, but intrinsic factor also. Since both HCl and intrinsic factor are required for the digestion and absorption of vitamin B12, malabsorption results.
Numerous reports have been published relating cases of hypergastrinemia in people with achlorhydria/pernicious anemia who were treated with high doses of Prilosec. As one author reviewing the published scientific literature on elevated gastrin levels understated, “The evidence indicates that chronic hypergastrinemia may not be totally benign.”
Elevated gastrin may also be a factor in some cases of human colorectal cancer, although the data are much fuzzier than they are for gastric adenocarcinoma. Nevertheless, it appears that the risk of developing carcinoids and gastric adenocarcinoma due to chronic hypergastrinemia may be increased if one possesses a specific gene. Whether acid-suppressing drugs can contribute to colorectal cancer remains “up in the air” at this time.


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