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.

Keywords: MEN1; PPI; gastric carcinoid; gastrinoma; hypergastrinemia; neuroendocrine tumor.

Figure 1

Fasting serum gastrin (FSG) concentration in Zollinger–Ellison syndrome (ZES) patients at NIH (n = 309) (A,B) and from the literature (n = 2229) (B). In (A), the FSG is expressed as log of concentration (left Y axis) with the numerical value in pg/mL (right Y axis), with upper limit of normal shown by the dotted line. In (B), the FSG levels from both the NIH and from literature patients are shown as fold over normal with normal FSG level indicated by the dotted line. Asterisks indicated statistically significant differences (p < 0.02) in two groups of patients for a given FSG level in (B). Figure is drawn from data in [24]. Note that 40% of ZES patients have FSG levels that overlap with those seen in non-ZES patients taking chronic proton pump inhibitors (PPIs).

Figure 2

Correlations between the fasting serum gastrin levels (FSG) and the gastric enterochromaffin-like cells (ECL) cell proliferative index in ZES patients from two NIH studies. (A,B) show data from patients with sporadic ZES (n = 106) whereas (C) shows data from a study of patients (n = 57) with MEN1/ZES. All patients had multiple gastric biopsies and the proliferative ECL index was calculated from the degree of ECL changes in all biopsies and correlated with the FSG level. In (A) all 106 sporadic disease patients were included (90 active, 16 cured) and in (B), only patients with FSG levels <5-fold increased were included, which are levels overlapping with those seen in nonZES patients taking chronic PPIs. (C) shows the data from the 57 patients with MEN1/ZES. In all cases, there is a highly significant correlation of the FSG levels with the degree of ECL cell proliferative change. In (B), the data shows there is no threshold for gastrin’s ability to stimulate ECL cell proliferative effects as was proposed in the past. Figures are drawn from the data in [25,61].

Figure 3

Examples of gastric ECL cell proliferative changes in ZES patients. In (A,B), results from gastric biopsies in two patients with MEN1/ZES are shown. In (A), a normal distribution of chromogranin A positive ECL cells in the oxyntic mucosa is shown. (B) shows a second MEN1/ZES patient a small intramucosal ECL-cell tumor (on the left), in association with an ECL-cell dysplastic lesion (in the center) and severe LH of ECl cells (on the right). In (C,D) are results from patients with sporadic ZES. (C) shows a normal ECL pattern with chromogranin staining and (D) shows micronodular and linear hyperplasia of ECL cells (in black) in a biopsy specimen of a patient with ECL cell dysplasia. Pictures are from Prof. C. Bordi (Univ. Parma) and made from data in [25,61]. Advanced ECL changes occurred in 53% of patients with MEN1/ZES with 2% showing dysplasia and 23% of patients have a gastric carcinoid found [61]. In sporadic ZES patients, 50% of patients had advanced ECL cell changes, 7% showed dysplasia, and none had a gastric carcinoid. The latter data show that advanced ECL changes including dysplasia can occur with prolonged chronic hypergastrinemia in man (mean duration of 13.2 yrs.) without any other contributing features such as the presence of MEN1, gastric mucosal atrophy, or gastric mucosal inflammation. 180X.

Figure 4

Effect of prolonged PPI treatment in ZES patients on body iron stores/levels (A) or serum vitamin B₁₂ and folate levels in two NIH (B). In (A), data from 109 ZES patients treated with antisecretory drugs for a mean of 10.2 years are shown (81% PPIs for 6 years, 8% histamine H₂ receptor antagonist, 10% cured, off all drugs). Results are shown for patients with or without advanced basal acid hyposecretion on the antisecretory drug. Normal values are shown by the dotted lines and means ± SEM are also shown for each group. (B) shows serum vitamin B₁₂ and folate levels in 108 ZES patients correlated with time of omeprazole treatment. The serum vitamin B₁₂ levels inversely correlated with the time of omeprazole treatment, whereas there was no effect on the serum folate levels. Figures are drawn from data in [27,253]. These data showed that prolonged chronic treatment in ZES patients did not affect serum iron levels or iron body stores, however there was a significant decrease in serum vitamin B₁₂ levels correlating with PPI treatment duration, but not serum folate levels.