Proton pump inhibitors (PPIs) have taken the place of histamine H2 receptor antagonist in the treatment of peptic ulcer disease, mainly due to their superior gastric acid suppression effect. Today, they are approved in many countries for not only the management of a variety of gastrointestinal disorders, such as gastric and duodenal ulcers, gastroesophageal reflux disease (GERD), reflux esophagitis, and Barrett esophagus, but also Helicobacter pylori eradication, prophylaxis for bleeding associated with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin, and pathologic hypersecretory conditions.1 Consequently, they are currently one of the most widely prescribed drugs worldwide.

In addition to their superior gastric acid suppression effect, PPIs have other advantages over H2 receptor antagonists. For example, PPIs are metabolized by the liver and do not require dose-adjustment based on renal function, and they are usually given as once-a-day prescription. These advantages and the early impression that they had encouraging safety profiles have contributed to the increased prescription of PPIs.

When PPIs are prescribed for peptic ulcer disease or H. pylori eradication, the duration of PPI-therapy is usually limited and short-term (<8 weeks); however, when used for GERD, Barrett esophagus, prophylaxis for bleeding associated with NSAIDs or low-dose aspirin­, and pathologic hypersecretory conditions, PPIs are usually prescribed for long periods without specified treatment goal. Also, with recent introduction of combination preparation of low-dose aspirin and a PPI, patients with ischemic heart disease and/or cerebral vascular diseases may continue a PPI for indefinite period, possibly lifelong.

Proton pump inhibitors were first introduced in 1989 and as their use has become prevalent and the restriction of the treatment periods has been less strict or abolished, adverse effects associated with their long-term use have been recognized. Although the evidence level sof most of the studies on the potential adverse effects associated with long-term PPI are not high enough to evaluate the causative association, comprehensive reviews on the safety of long-term PPI use have been published.1-3 Long-term use of PPIs is reported to be associated with conditions such as osteoporosisand bone fracture, Clostridioides difficile (formerly Clostridium difficile) infection, small intestinal bacterial overgrowth, collagenous colitis, chronic kidney disease, pneumonia, dementia, and deficiencies of micronutrients such as calcium, iron, magnesium, and vitamin B12, and the list of such conditions is increasing. Among these associations, the relationships between PPIs with hypomagnesemia, vitamin B12 deficiency, and small intestinal bacterial overgrowth appear likely; however, others are unclear due to lack of high-quality evidence, confounding factors, and unclear pathophysiological causality. Moreover, PPI treatment for patients involved in the previous studies is necessarily limited and may not be long enough to evaluate the real long-term adverse effects of treatments that will be continued for decades. It is possible that longer observation period may reveal causative associations. In particular, accumulation of continuous small deficit of micronutrients may eventually reach the level which can cause clinically significant consequences associated with long-term PPI treatment. As the decrease in absorption of micronutrients is subtle or minimal and the progress of the deficit may be insidious, it may take years for a micronutrient to decrease to a clinically meaningful level. In such case, it is likely that signs and symptoms related to the deficit are not overt or are not noticed until the deficiency becomes profound. We still do not know what happens to patients who have taken PPIs for longer than 30 years. In fact, we experienced a case of iron deficiency anemia which developed after 25 years of PPI use.4 Further extended use of PPIs may prove that conditions whose association with long-term PPIs is suggested but not clear have in fact a causative relation. It should be mentioned here that the effects of PPIs may differ among individuals possibly due to the interindividual variability of CYP2C19 gene and the composition of daily diet. Interaction with other drugs may also have to be taken into consideration. Thus, there might be considerable differences in the long-term effects of PPIs among individuals, making generalized conclusion rather difficult.

In this issue of Polish Archives of Internal Medicine (Pol Arch Intern Med), Kaczmarczyk et al5 describe another aspect of long-term effects of PPIs. They report higher prevalence of anemia and leucopenia, lower serum iron level, and higher copper and zinc levels among long-term PPI users, with the data on the serum selenium level, and correlations of the findings. While it should be noted that the duration of PPI therapy is between 3 and 10 years and may not be long enough to determine the true long-term effects as discussed earlier, they have already observed emerging effects of “long-term” PPIs and present a new insight that longer-term PPI use may lead to disturbance or imbalance of micronutrients which are not known to be affected by long-term PPI use so far. Larger and more comprehensive studies with longer treatment periods are expected to confirm or refute their findings and also to verify the observation that suppression of gastric acid is not the only factor associated with long-term adverse effects.

Newer and more potent PPIs have been successively developed, achieving more profound suppression of gastric acid. We are going into an unknown realm of long-term use of more potent PPIs and should be prepared to encounter unexpected adverse effects. A recommendation for routine monitoring and prophylaxis is proposed for some of the adverse effects.3 However, as prospective studies in which a large number of individuals are followed for decades are not realistic and we will hardly know the true “long-term” effect of PPIs, they should be prudently prescribed only when necessary and at the lowest dose for the shortest term possible, balancing the benefits and adverse effects.