Abstract
The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25–70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10–20 years). Zollinger–Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.
Highlights
Proton pump inhibitors (PPIs) inhibit gastric H+K+ATPase, which is required for gastric acid secretion, and are one of the most widely used classes of drugs in the world [1,2]
This result agrees with a number of other studies of sporadic Zollinger–Ellison syndrome (ZES) patients in which no gastric carcinoid tumor was found [36,62,158,161,166,167,168,175]. This result is in contrast to a few case reports of patients with sporadic ZES who had gastric carcinoid tumors found [23,47,71,72,138, 171,176,177,178,179,180]. These results show that, despite prolonged chronic hypergastrinemia averaging 14 years in the large NIH study reviewed above [25] and the fact that the ZES patients in more than half of the cases had high fasting serum gastrin (FSG) levels at least double that seen typically in patients being treated with PPIs, with many ZES patients with FSG > 5–10 levels (Figure 1), the occurrence of gastric carcinoids in the sporadic ZES patients was very uncommon
ZES is a useful model to assess the effect of very long/lifetime PPI treatment, because
Summary
Proton pump inhibitors (PPIs) inhibit gastric H+K+ATPase, which is required for gastric acid secretion, and are one of the most widely used classes of drugs in the world [1,2]. Each of these two areas will be reviewed from studies in ZES patients to provide insights into the increasing debate on the long-term safety of PPIs and risks of very long-term chronic hypergastrinemia. Before this is addressed, it is important to understand why chronic hypergastrinemia is considered a health concern, what are the specific safety concerns being raised currently with PPIs, and how the study of ZES is well-versed to address some of these issues
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