Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger–Ellison Syndrome

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.

Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids—What Is the Relationship?

“…Long-term human use of PPIs leads to hypergastrinemia in almost all cases, with fasting serum gastrin (FSG) levels increasing 3 to 5-fold in most subjects, but to much higher levels in 10% to 30% of cases [11]. Higher levels are seen in females and in those with atrophy of the gastric corpus due to CAG, whether auto-immune or due to Helicobacter pylori [27].…”

“…In more recent classifications, tumors with a Ki-67 index <3% are designated as Grade 1, those with a Ki-67 index between 3% and 20% as Grade 2, and those with an index >20% as Grade 3 [10]. In these classifications, type-1 tumors are gastrin-dependent, sporadic, well-differentiated, arise in chronic hypochlorhydric states, comprise 70% to 80% of gastric carcinoids, and metastasize in <10% of cases [11]. Most are classified as Grade 1 (G1) on the WHO scale, with a Ki-67 index (if any) of <3%: they regress with resection of the gastric antrum, the location of the G-cells, which produce the gastrin.…”

“…Most are classified as Grade 1 (G1) on the WHO scale, with a Ki-67 index (if any) of <3%: they regress with resection of the gastric antrum, the location of the G-cells, which produce the gastrin. Type-2 gastric carcinoids occur in the presence of gastrinoma, primarily in those with MEN-1/ZES, rarely in uncomplicated sporadic ZES, comprise 5%-6% of gastric carcinoids, are gastrin-dependent, and malignant in 10%-30% of cases [11]. Type-3 tumors are gastrin-independent, sporadic, well-differentiated, comprise 14%-25% of gastric carcinoids, and 25%-40% are malignant.…”

“…Type-3 tumors are gastrin-independent, sporadic, well-differentiated, comprise 14%-25% of gastric carcinoids, and 25%-40% are malignant. Type-4 tumors are sporadic, gastrin-independent, poorly differentiated, and metastasize in 50%-100% of cases [11]. There are rare gastric carcinoids that do not fit into this classification [12].…”

“…The effects of hypoacidity and consequent hypergastrinemia on gastric neoplasia have been reviewed in detail elsewhere, including results from a wide variety of experiments in animal models [11,13,22,23]. Of particular note, the prolonged use of proton pump inhibitors (PPIs) or of an insurmountable H2-antagonist loxtidine, induced malignant ECL-derived tumors in the oxyntic mucosa of rodents.…”