Rebound Acid Hypersecretion after Withdrawal of Long-Term Proton Pump Inhibitor (PPI) Treatment-Are PPIs Addictive?

Abstract

Proton pump inhibitors (PPIs) are widely used in the long-term treatment of gastroesophageal reflux disease (GERD) and other upper gastrointestinal disorders, such as the healing of peptic ulcers and/or prophylactic treatment of peptic ulcers. PPIs are also widely used as symptomatic treatment in patients with functional dyspepsia. One of the adverse effects of the long-term use of PPI is rebound acid hypersecretion (RAHS), which can occur after the withdrawal of PPI therapy due to a compensatory increase in gastric acid production. Mechanisms of the RAHS have been well established. Studies have shown that pentagastrin-stimulated acid secretion after the discontinuation of PPIs increased significantly compared to that before treatment. In healthy volunteers treated with PPIs, the latter induced gastrointestinal symptoms in 40-50% of subjects after the discontinuation of PPI therapy but after stopping the placebo. It is important for practicing physicians to be aware and understand the underlying mechanisms and inform patients about potential RAHS before discontinuing PPIs in order to avoid continuing unnecessary PPI therapy. This is important because RAHS may lead patients to reuptake PPIs as symptoms are incorrectly thought to originate from the recurrence of underlying conditions, such as GERD. Mechanisms of RAHS have been well established; however, clinical implications and the risk factors for RAHS are not fully understood. Further research is needed to facilitate appropriate management of RAHS in the future.

Keywords: discontinuation; gastrin; proton pump inhibitors; rebound acid hypersecretion; withdrawal.

Figure 1

Physiological mechanisms of rebound acid hypersecretion: (a) under normal physiological conditions, protein in meals stimulates the G-cells to release gastrin into the blood. Gastrin stimulates the enterochromaffin-like (ECL) cells to release histamine. The histamine then stimulates acid-producing parietal cells. This is the gastrin–ECL axis, the main stimulatory pathway of gastric acid secretion. The over-production of acid is prevented by negative feedback inhibition by intragastric acidity as low antral pH inhibits gastrin release via somatostatin from D-cells. (b) Protein pump inhibitors (PPIs) inhibit gastric acid secretion by binding covalently to active proton pumps on the parietal cells. This prevents acid secretion and leads to hypoacidity (higher pH level). Thus, somatostatin-mediated negative feedback of gastrin release on antral G-cells is inhibited, which leads to hypergastrinemia, and gastrin exerts a trophic effect on gastric mucosa, causing enterochromaffin-like (ECL) hyperplasia. (c) The measurement of CgA levels in the blood can be a useful tool for monitoring ECL cell hyperplasia secondary to treatment with PPIs; following PPI discontinuation, the recovery of acid secretion can be exaggerated. Hypergastrinemia secondary to PPI therapy is associated with acid hypersecretion or the so-called rebound acid hypersecretion phenomenon. ECL cell: enterochromaffin-like cell. These figures were adapted from Helgadottir 2009 [29].

Figure 1

Physiological mechanisms of rebound acid hypersecretion: (a) under normal physiological conditions, protein in meals stimulates the G-cells to release gastrin into the blood. Gastrin stimulates the enterochromaffin-like (ECL) cells to release histamine. The histamine then stimulates acid-producing parietal cells. This is the gastrin–ECL axis, the main stimulatory pathway of gastric acid secretion. The over-production of acid is prevented by negative feedback inhibition by intragastric acidity as low antral pH inhibits gastrin release via somatostatin from D-cells. (b) Protein pump inhibitors (PPIs) inhibit gastric acid secretion by binding covalently to active proton pumps on the parietal cells. This prevents acid secretion and leads to hypoacidity (higher pH level). Thus, somatostatin-mediated negative feedback of gastrin release on antral G-cells is inhibited, which leads to hypergastrinemia, and gastrin exerts a trophic effect on gastric mucosa, causing enterochromaffin-like (ECL) hyperplasia. (c) The measurement of CgA levels in the blood can be a useful tool for monitoring ECL cell hyperplasia secondary to treatment with PPIs; following PPI discontinuation, the recovery of acid secretion can be exaggerated. Hypergastrinemia secondary to PPI therapy is associated with acid hypersecretion or the so-called rebound acid hypersecretion phenomenon. ECL cell: enterochromaffin-like cell. These figures were adapted from Helgadottir 2009 [29].