How do ppis cause hypomagnesemia

The association between proton-pump inhibitors and metabolism of magnesium was addressed in 14 case-control, cross-sectional studies, as given in Table 2. An association was found uniquely in 10 of them. Six reports found that the use of proton-pump inhibitors is associated per se with a tendency towards hypomagnesemia [ 8 , 10 , 11 , 13 , 14 , 18 ].

Two reports found that the tendency towards hypomagnesemia is more pronounced in patients concurrently treated with either diuretic [ 13 , 18 ] or carboplatin and cisplatin [ 11 ]. Danziger et al.

Furthermore, two reports found a relevant tendency to hypomagnesemia in patients with poor renal function treated with proton-pump inhibitors [ 5 , 15 ]. William et al. Finally, three of the aforementioned studies did not find any relationship between magnesium and histamine type-2 receptor antagonists [ 7 , 14 , 18 ].

The reports submitted to the Adverse Event Reporting System of the United States Food and Drug Administration were recently examined to address the association between use of proton-pump inhibitors and hypomagnesemia [ 63 ]. Between and , 66, subjects were identified as experiencing at least one adverse effect while taking a proton-pump inhibitor.

Finally, there was a strong association between occurrence of hypomagnesemia and that of hypocalcemia or hypokalemia. Two thirds of the hypomagnesemia cases occurred in subjects treated with omeprazole or esomeprazole, the most frequently prescribed proton-pump inhibitors. This work brings together the most recent literature and some reports identified exclusively from the search engine Google Scholar.

Its results, acquired both in individual case reports and in case-control, cross-sectional studies, support the hypothesis that management with proton-pump inhibitors may cause hypomagnesemia along with hypomagnesiuria, hypocalcemia, and hypokalemia see the following list.

This tendency is more pronounced in patients concomitantly treated with cisplatin, carboplatin, and especially diuretics and in those with poor renal function.

Consider the following. The concurrent demonstration of both magnesium deficiency and hypomagnesiuria suggests that impaired intestinal magnesium absorption is the culprit. This electrolyte abnormality recovers within 4 days after discontinuing the drug; it recurs upon readministration or after replacement with another proton-pump inhibitor [ 64 ], but it does not develop with other acid suppressants such as histamine type-2 receptor antagonists.

Hypomagnesemia was mostly accompanied by hypocalcemia and normal or low parathyroid hormone levels, confirming the existence of a state of secondary hypoparathyroidism in the most severely hypomagnesemic patients [ 65 ].

A further common laboratory finding was hypokalemia, a recognized consequence of hypomagnesemia [ 65 ]. In the few individual cases available for such an analysis, no significant correlation was noted between circulating magnesium and hypocalcemia or hypokalemia. At least two factors might account for this unexpected observation.

First, there are sometimes differences among laboratories with respect to total magnesium determination in blood [ 65 ]. Furthermore, circulating magnesium exists in the ionized, biologically active state and in the undissociated form, either bound to albumin or complexed to anions such as bicarbonate, citrate, and phosphate [ 65 ].

At least three limitations of our study should be mentioned. First, the analysis results rather from the small number of reported subjects affected by proton-pump inhibitor associated hypomagnesemia. Second, because of the scant information available on the clinical presentation of magnesium deficiency, the present study does not address this issue.

Third, the underlying mechanisms require further investigations. Recognition and management of hypomagnesemia secondary to long-term treatment with proton-pump inhibitors mainly rest on two pillars: first, blood magnesium monitoring at least in patients with symptoms or signs consistent with magnesium deficiency, in those concurrently treated with other agents that may lower magnesium level, and in those with poor renal function; second, in patients with hypomagnesemia, switching to a histamine type-2 receptor antagonist may be attempted.

Further studies are required to identify whether magnesium supplements or sucralfate might be prescribed in subjects with proton-pump inhibitor associated hypomagnesemia. Simone Janett, the principal investigator, conceptualized and designed the study, performed the review of the literature, drafted the initial paper, and approved the final paper as submitted.

Pietro Camozzi conceptualized and designed the study, performed the review of the literature, designed the figures, and approved the final paper as submitted. Peeters conceptualized the study, substantially participated in the review of the literature, and approved the final paper as submitted. Sebastiano A. Lava contributed to the study design, supervised the review of the literature, prepared the figures, and wrote the final paper as submitted.

Giacomo D. Simonetti and Barbara Goeggel Simonetti supervised the review of the literature and approved the final paper as submitted. Mario G. Bianchetti, the senior author, conceptualized and designed the study, supervised the review of the literature and the preparation of the paper, performed statistical analysis, and wrote the final paper as submitted.

Gregorio P. Milani conceptualized and designed the study, supervised the review of the literature, the statistical analysis, and wrote the final paper as submitted. Simone Janett and Pietro Camozzi contributed equally to this work. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Peeters, 1 Sebastiano A. Lava, 2 Giacomo D. Bianchetti , 1 and Gregorio P. Academic Editor: Haruhiko Sugimura.

Received 22 Dec Accepted 16 Apr Published 04 May Abstract In , hypomagnesemia was first described as a complication of proton-pump inhibitors. Introduction First introduced in the late s, proton-pump inhibitors are widely used for the management of conditions related to gastric acid secretion such as duodenal and gastric ulcer, reflux esophagitis, and gastroesophageal reflux disease [ 1 ].

Results 3. Search Results The initial search revealed publications, of which remained after excluding duplicates Figure 1. Figure 1. Flowchart of the literature search process. Five of the 60 eligible reports had been identified exclusively from the Web-based search engine Google Scholar. Table 1. Numerical data are presented as median and interquartile range which extends from the value at centile 25 to that at centile 75 and includes half of the data points and categorical data as relative frequency.

Figure 2. Relationship between circulating magnesium and total calcium left panel or potassium right panel in patients with proton-pump inhibitor associated hypomagnesemia. None of the correlations was found to be significant. The horizontal dotted lines denote the threshold level of hypocalcemia 2.

Reference Country Patients Results Alhosaini et al. Use of histamine type-2 receptor antagonists with or without diuretics was not associated with hypomagnesemia El-Charabaty et al. Concurrent treatment with cisplatin or carboplatin further exacerbated hypomagnesemia Koulouridis et al. Use of histamine type-2 receptor antagonists was not associated with hypomagnesemia Sumukadas et al. Use of histamine type-2 receptor antagonists was not associated with hypomagnesemia.

Table 2. As detailed in Table 1 , demographic, clinical and laboratory characteristics of our cohort were fully consistent with those expected in TdP patients based on established epidemiological data. In three patients under extended home PPI therapy, the molecule was changed during hospitalization, before TdP development from oral lansoprazole or pantoprazole to intravenous pantoprazole in two cases; from oral omeprazole to oral pantoprazole in the other one.

Notably, none of the intravenously-treated patients showed hypomagnesemia. Although these findings suggest that diuretics alone, differently to PPIs alone, were not sufficient to cause magnesium depletion, nevertheless diuretics may exacerbate PPI-associated magnesium reduction when administered in association.

Despite a specific investigation, no any significant impact of other common causes of hypomagnesemia was found in our cohort of patients see Supplementary Results for more details.

Figure 2. Horizontal dotted line indicates the lower limit of reference values for serum magnesium levels, i. Figure 3. A Serum calcium levels. Horizontal dotted line indicates the lower limit of reference values for calcium levels, i.

B Serum potassium levels. Horizontal dotted line indicates the lower limit of reference values for potassium levels, i. C Serum sodium levels. Horizontal dotted line indicates the lower limit of reference values for sodium levels, i. Table 3. As regards the other QTc-prolonging risk factors of acquired origin, individually considered, no significant differences in terms of concomitant diseases, both cardiac and extra.

Notably, statistical significance of this difference was lost if hypomagnesemia, i. Nevertheless, when we restricted the analysis to patients with full data only, i. Conversely, PPI treatment did not seem to affect the short-term outcome in our cohort of patients. As shown in Figure 4A , circulating magnesium levels were significantly lower in TdP vs. Figure 4. Comparison of serum magnesium levels in TdP patients and controls. Horizontal dotted line indicates the lower limit of reference values for magnesium levels, i.

Magnesium, representing the most abundant intracellular divalent cation, plays a key role in regulating potassium and calcium channels in the heart Gupta et al. Experimental studies demonstrated that cytosolic magnesium promotes repolarization of myocardial cells via modulating effects on several potassium currents, including the rapid component of the delayed rectifier potassium current IKr and transient outward current Ito Kelepouris et al.

Moreover, magnesium markedly inhibits the L long-lasting -type calcium current ICaL , possibly as a result of a direct block of the L-type-calcium channel pore by external magnesium or via modification of the activity of protein kinases or phosphoprotein phosphatases Zhao et al. Moreover, ICaL is the main depolarizing current that generates early after depolarizations EADs , in turn representing the primary electrophysiological mechanism underlying TdP development Viskin, ; El-Sherif and Turitto, This supports the fact that hypomagnesemia is a recognized risk factor for QTc prolongation and TdP Viskin, ; El-Sherif and Turitto, , , as well as the clinical evidence that magnesium sulfate is very effective for the treatment of TdP thus being considered the standard of care for this arrhythmia Drew et al.

PPI-induced hypomagnesemia, for the first time described in , has been increasingly recognized in the last years as a potentially life-threatening adverse event whose actual incidence is probably largely underestimated Famularo et al. Until PPI interruption, hypomagnesemia is refractory to oral or parenteral magnesium replacement irrespective of high-dose supplementation; when the PPI is stopped, serum magnesium levels returned to normal in less than 2 weeks ; Famularo et al.

However, hypomagnesemia may recur after re-challenge with the same or a different PPI. In these patients, when prolonged antiacid treatment is needed, prescription of a H 2 histamine receptor-blocker H 2 -blocker may be an appropriate therapeutic alternative Famularo et al. In fact, although mechanisms of PPI-induced hypomagnesemia are not clear, hypochlorhydria does not seem to be involved.

Accordingly, recent data suggest that carriers of TRPM6 polymorphisms are at increased risk Hess et al. The results of the present study suggest that the phenomenon is significantly more common than reported, being probably underestimated because in the clinical practice PPIs do not currently receive the due attention as a factor potentially contributing to QTc prolongation and TdP.

Consistently with literature data Famularo et al. Our data seem also to confirm that the risk of PPI-induced hypomagnesemia further increases when PPIs are co-administered with diuretics, probably as a result of an enhancement of the renal loss of magnesium.

Conversely, although in PPI users hypomagnesemia has been reported to be often accompanied by hypocalcemia and hypokalaemia Famularo et al. Another important suggestion arising from the present study is that PPI-associated changes in magnesium levels have a relevant clinical impact by increasing the risk of developing TdP in these patients. In fact, PPI users showed a significantly higher mean total number of QTc-prolonging risk factors per patient when compared to non-users.

Accordingly, when hypomagnesemia was excluded from the total risk factor count, this difference was no longer statistically significant. This view, further supporting the role of PPI-induced hypomagnesemia as a risk factor for TdP, warrants specific investigation. Although our data point to the conclusion that PPIs can increase the risk of TdP by inducing hypomagnesemia, the involvement of additional, possibly molecule-related mechanisms could not be ruled out.

While short-term standard dose PPI treatment has low risk, long-term PPI use may complicate health conditions in high risk patients for hypomagnesemia including elderly patients [46]. The inter-study differences in the proportion of patients with hypomagnesemia in our meta-analysis may suggest that there are patients with increased susceptibility to PPI-induced hypomagnesemia. Considering the excellent safety profile of PPIs, risk identification and stratification for PPI-induced hypomagnesemia may be more helpful for clinical practice, rather than investigation of PPI-induced hypomagnesemia in the general population.

However, the study only included PPI users whose serum magnesium levels were available, and therefore, selection bias may be a concern. A population based study with regular checkup for serum magnesium level may be needed for clarifying the high risk patients for PPI-induced hypomagnesemia. In our study, we conducted the two types of subgroup analysis.

The former was subgroup analysis for studies which included hospitalized patients only, while the latter was subgroup analysis according to the cut-off value of serum magnesium level. In the former subgroup analysis, statistical significance between PPI use and the risk of hypomagnesemia was not shown. Although the subgroup included only hospitalized patients, the variation among the studies was still existed.

In the latter subgroup analysis, PPI use increased the risk of hypomagnesemia in the studies whose cut-off value was 1. These results implied that PPI-induced hypomagnesemia might not be as severe as we were concerned; however, further studies would be needed for assessing the severity of PPI-induced hypomagnesemia. Although this is the first meta-analysis which demonstrated that PPI use could increase the risk of hypomagnesemia, there are several limitations.

First, this is the meta-analysis for observational studies rather than randomized controlled trials. Magnesium assessment in a large database is usually healthcare-driven and potentially biased. In addition, dyspepsia may lead to prescribing PPIs as well as deficient food intake with low magnesium ingestion. Furthermore, serum magnesium was not usually evaluated in clinical practice. Although we conducted a meta-analysis using the adjusted ORs in the included studies, potential issues of confounding variables may be exist.

The conclusion from the meta-analysis for observational studies should be interpreted carefully. Second, the significant heterogeneity among the included studies was additional obvious limitation. Through our systematic review and meta-analysis, we found that the proportion of patients with hypomagnesemia depended on the study settings including patient population and characteristics.

Prospective cohort studies will be needed to evaluate severity of PPI-induced hypomagnesemia and to identify high risk group for PPI-induced hypomagnesemia. Third, we could not assess the risk of PPI-induced hypomagnesemia according to the amount or duration of usage of PPIs because available data were limited in the included studies.

Despite of these limitations, our meta-analysis showed that PPI use may increase the risk of hypomagnesemia. Well-designed, prospective cohort studies, which include regular serum magnesium monitoring, would provide more conclusive results.

Contributed to the writing of the manuscript: CHP. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Background Although many case reports have described patients with proton pump inhibitor PPI -induced hypomagnesemia, the impact of PPI use on hypomagnesemia has not been fully clarified through comparative studies.

Results Nine studies including , patients were analyzed. Conclusions PPI use may increase the risk of hypomagnesemia. Funding: The authors have no funding or support to report. Introduction Proton pump inhibitors PPIs are a mainstay of treatment for acid-related diseases, including gastroesophageal reflux disease, functional dyspepsia, and peptic ulcer disease [1] — [5].

Study selection In the first stage of the study selection, the titles and abstracts of papers returned by our keyword search were examined to exclude irrelevant articles. Data extraction Using a data extraction form developed in advance, two reviewers C. Outcomes assessed Our primary analysis focused on assessing the risk of hypomagnesemia among users of PPIs.

Results Study selection A flow diagram for our systematic review is shown in Fig. Download: PPT. Figure 1. Flow diagram of studies included in the meta-analysis. Table 1. Characteristics of studies included in the meta-analysis. Risk of hypomagnesemia The cut-off value of serum magnesium level for defining hypomagnesemia was 1.

Subgroup analysis We performed pre-planned subgroup analysis of studies, based on the hospitalization of patients. Figure 3. Subgroup analysis for studies which included only hospitalized patients. Figure 4. Subgroup analysis according to the cut-off value of serum magnesium levels. Discussion Intracellular magnesium is an important cofactor for enzymatic reactions, and is critical for energy metabolism involving adenosine triphosphate [19]. Supporting Information. This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers.

This article has been cited by other articles in PMC. Abstract Magnesium deficiency can cause a variety of symptoms, including potentially life-threatening complications such as seizures, cardiac arrhythmias and secondary electrolyte disturbances.

Keywords: Hypomagnesemia, Proton pump inhibitor, Gastroesophageal reflux disease, Drug adverse effect, Laparoscopic fundoplication. Open in a separate window. Figure 1. COMMENTS Case characteristics A year old male with gastroesophageal reflux disease and persistent severe hypomagnesemia demanding weekly intravenous magnesium infusions. Clinical diagnosis Extensive work-up did not reveal any other cause of hypomagnesaemia. Differential diagnosis Gastrointestinal or renal disease causing either impaired absorption or increased excretion of magnesium.

Laboratory diagnosis Initially the patient had severe hypomagnesemia 0. Pathological diagnosis Biopsies taken from terminal ileum and colon during colonoscopy were normal. Treatment The patient underwent a successful laparoscopic fundoplication, and his serum magnesium levels again normalized following PPI withdrawal after the surgery.

Related reports PPI-induced hypomagnesemia PPIH was first described in , and subsequently several other case reports have demonstrated the association. Term explanation PPIH is a rare, but potentially serious adverse effect where persistent severe hypomagnesemia is associated with of long-term PPI treatment. Peer-review The manuscript describes surgical option in the management of hypomagnesemia induced by PPIs.

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