Continuous Proton Pump Inhibitor Therapy and Associated the Associated Risk of Recurrent Mconald
Cureus. 2021 Jan; 13(1): e12759.
Adverse Effects Associated with Proton Pump Inhibitor Use
Monitoring Editor: Alexander Muacevic and John R Adler
Marcel Yibirin
1 Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, USA
Diana De Oliveira
2 Department of Research, Foundation for Clinic, Public Health, and Epidemiological Research of Venezuela (FISPEVEN), Caracas, VEN
Roberto Valera
3 Department of General Surgery, Cleveland Clinic Florida, Weston, USA
Andrea E Plitt
4 Critical Care, Dr. Ignacio Pirovano Hospital, Buenos Aires, ARG
Sophia Lutgen
5 Internal Medicine, Dr Juan A. Fernández Hospital, Buenos Aires, ARG
Abstract
Proton pump inhibitors (PPIs) marked a before and after in the management of gastric acid‐related disorders since their introduction to the market in 1989. Due to a novel, highly effective mechanism of action blocking the last converging step of gastric acid secretion by parietal cells and very few and mostly tolerable side effects, these drugs quickly displaced other pharmacological compounds such as H2 antagonists as the first treatment choice for peptic ulcer disease, gastroesophageal ulcers, Zollinger-Ellison syndrome, nonsteroidal anti-inflammatory drug-associated ulcers, and eradication of Helicobacter pylori, leading to an exponential increase in their prescription up to now. However, widespread PPI use has led to emerging evidence of long-term adverse effects not described previously, including increased risk of kidney, liver, and cardiovascular disease, dementia, enteroendocrine tumors of the gastrointestinal tract, susceptibility to respiratory and gastrointestinal infections, and impaired absorption of nutrients. Although the evidence published thus far has not established strong correlations, it has been relevant enough to raise new questions about PPIs' safety profile and reconsideration of their clinical indications. Hence, the aim of this review is to evaluate the association between PPI use and the risk of serious adverse effects given increasing concerns about the overuse of PPIs in the general population.
Keywords: proton pump inhibitors, adverse effects
Introduction and background
Proton pump inhibitors (PPIs) are widely used irreversible inhibitors of H+/K+ adenosine triphosphatase (ATPase), the final step of gastric acid secretion by parietal cells in the stomach. Over the past few decades, the use of these drugs has increased in many countries due to the expansion of their role as drugs of choice in the treatment of gastric acid‐related disorders such as peptic ulcer disease, gastroesophageal ulcers, Zollinger-Ellison syndrome, nonsteroidal anti-inflammatory drug-associated ulcers, and eradication of Helicobacter pylori. In the United States, the use of PPIs doubled from 3.9% in 1999 to 7.8% in 2012. However, numerous studies have demonstrated overprescription of PPIs [1]. In general, PPIs are believed to have few adverse effects, as they are generally well tolerated. Patients have experienced few minor side effects of short-term PPI use, such as headache, rash, dizziness, and gastrointestinal symptoms including nausea, abdominal pain, flatulence, constipation, and diarrhea. In general, physicians are not concerned about serious side effects of PPIs at approved dosing during a brief treatment time of about two weeks, but as the use of these drugs increases, reports of their side effects are increasing, particularly with long‐term use [2]. In recent studies, researchers advised that PPIs should be used for the shortest time period at the smallest effective dose [3], as infections, impaired absorption of nutrients, dementia, kidney disease, and hypergastrinemia-related side effects are emerging as possible consequences of long-term use [2]. Therefore, the aim of this review is to describe the association between PPI use and the risk of serious adverse effects given the increasing concerns about the overuse of PPIs in the general population (Figure 1).
Figure 1
Side effects associated with the use of proton pump inhibitors
Review
Kidney disease
Since 1992, case reports have linked PPI use with acute kidney injury [1], and recently, two studies connected PPI use with an excessive risk of chronic kidney disease (CKD), which was not explained solely by the risk of acute kidney injury, with evidence that patients who used PPIs for longer durations had higher risk of CKD [4]. Apparently, patients with established diagnoses of CKD may progress rather quickly on PPI therapy [5-7]. The main mechanism leading to renal pathology due to PPI use could be acute interstitial nephritis. More than half of the patients who suffered PPI-induced acute interstitial nephritis [7] did not fully recover, suggesting that PPI-induced CKD is due to progression of acute interstitial nephritis with inflammatory interstitial infiltrates and edema to chronic interstitial scarring and tubular atrophy. Taken together, these findings represent good evidence that PPIs cause acute interstitial nephritis and some evidence that they also increase the risk of CKD. Initially, physicians considered PPIs to also inhibit other than gastric proton pumps, such as the ones in the renal tubule, but definitive evidence of this in a clinical setting is lacking [8-9].
Infections
Gastrointestinal Infections
PPI use has been linked with increased risk of both incidental and recurrent Clostridium difficile infections [10-13]. Acid secretion by parietal cells is an important immunological barrier in the gastrointestinal tract, which is why hypochlorhydria generated by the inhibition of gastric acid secretion increases the risk of bacterial colonization and altered intestinal flora and susceptibility to enteric infections [2]. Studies have demonstrated that intense suppression of gastric acid secreation is associated with increased risk of Clostridium difficile infection. Authors reported that more than two-thirds of inpatient acid-suppressive prescriptions are not strictly indicated and the number of Clostridium difficile infection cases in the United States is in the tens of thousands per year [14]. Authors have reported other enteric infections, such as non-typhoid Salmonella and Campylobacter infections [1-2,15], the latter of which has been racing [2].
Respiratory Infections
Pneumonia has been widely associated with PPI use, especially over the short term (usually fewer than 30-90 days). However, a recent meta-analysis demonstrated that this association may be overestimated [16]. The most likely explanation for the increased risk of respiratory infections with PPI use is that PPI-induced hypochlorhydria increases microaspiration of gastric contents, which increases lung colonization and the subsequent incidence of pneumonia [2]. PPI use also maybe associated with an increased risk of coronavirus disease 2019 (COVID-19), as authors have reported that patients using these drugs had higher odds of testing positive for COVID-19 than did patients not taking PPIs [17]. Coronaviruses are easily destroyed by an acidic gastric pH, although the impact of acid suppression is unclear. Previously reported data suggested that the infectivity of severe acute respiratory syndrome coronavirus 1 was reduced in individuals with a gastric pH of up to 3 [17]. Furthermore, researchers have shown coronaviruses to survive in individuals with more basic gastric pH levels, including those in the range created by the use of drugs like omeprazole and esomeprazole [17]. Current and past PPI use were associated with poor outcomes of COVID-19. However, this PPI use did not increase susceptibility to severe acute respiratory syndrome coronavirus 2 infection [16]. Receptors for COVID-19 (ACE-2) are found throughout the gastrointestinal tract, making plausible the hypothesis that PPI users may be more vulnerable than nonusers to the effect of high viral loads [16].
Gastrointestinal malignancies
Because PPIs decrease gastric acid secretion, compensatory raising of gastrin levels in patients has a proliferative effect on the growth of enterochromaffin-like cells, explaining the association of PPIs with development of neuroendocrine tumors and carcinomas of the gastrointestinal tract [18-20]. Another related mechanism is that PPIs facilitate gastric pan-colonization by Helicobacter pylori due to a decrease in the normal stomach acidic environment [1]. Numerous mechanistic studies suggested that hypoacidity and hypergastrinemia increase the risk of gastric cancer in the corpus/fundus, which was supported by epidemiological studies.
Liver disease
PPI use has been linked with increased risk of cirrhosis-related complications such as hepatic encephalopathy, spontaneous bacterial peritonitis, and liver cancer [21-24]. These effects appear to be related to chronic PPI use, as patients who underwent more than one year of follow-up after initiating treatment with PPIs had twice the risk of hepatocellular carcinoma than did those with no more than one year of follow-up [3]. The mechanism of liver injury associated with PPI use, is not completely understood, although investigators observed that H+/K+ ATPase inhibition leads to intestinal bacterial overgrowth and an altered intestinal microbial composition [25], which may lead to increased portal venous concentrations of several potentially harmful substances, including secondary bile acids [26]. PPIs are metabolized in the liver; therefore, patients with liver disease may be at risk for increased hepatotoxicity, which can lead to hypergastrinemia-induced carcinogenic effects, especially on liver cells [27-28]. Finally, the authors reported that after exposure to PPIs, cultured human liver cells exhibited gene expression similar to well-known carcinogens in the liver [29].
Fracture risk
Increased fracture risk due to PPI intake is a controversial topic [30]. Retrospective studies have suggested the existence of a dose-dependent relationship between PPIs and decreased bone mineral density, leading to an increase in fracture risk, especially hip fractures. The risk appears to be higher in patients with a risk factor for osteoporosis, such as renal dysfunction. Routine prophylaxis for osteoporosis is suggested for PPI users to preventosteoporotic fractures [30-32]. However, more recent prospective studies showed no significant changes in bone mineral density or fracture risk in PPI users over the short to medium term [33,34]. Proposed mechanisms that link long-term PPI-based therapy with decreased bone mineral density include hypochlorhydria-associated malabsorption of calcium (absorption of which is indispensable to maintaining bone microstructure), gastrin-induced parathyroid hyperplasia, and inhibition of bone resorption by blocking local H+/K+ ATPase [35-37].
Dementia
Overall, data on the association between PPI use and dementia risk are conflicting. Physicians have yet to come to a consensus on the role of PPIs and the associated risk of dementia. Even with uncertainty about the mechanism, most cases of brain dysfunction in PPI users are reported to be associated with chronic administration of PPIs [38]. Some PPIs, such as lansoprazole, esomeprazole, and pantoprazole, have been linked with neurological side effects, such as headaches and dizziness/vertigo. Less common reported side effects involving the central nervous system include depression, diplopia, disturbed sleep, drowsiness, insomnia, nervousness, tremor, sensory and perceptual abnormalities (e.g., hallucinations), and delirium [39]. Although the mechanisms are not completely understood, the neurological effects of PPIs appear to be explained by the influence in ionic pumps controlling the membrane potential in neurons [38]. The lysosomes of patients taking PPIs seem to be less acidic than those of patients not taking them, which may make cells less able to degrade amyloid-beta protein, the principal substance that accumulates in the brain in patients with Alzheimer's disease [40-41]. Other hypotheses include that PPI and H2 receptor antagonist use have indirect effects related to systemic abnormalities (i.e., magnesium and vitamin B12 deficiency).
Cardiovascular disease
Over the past decade, PPI use has been associated with cardiovascular morbidity and mortality [42]. Increased risk of major acute cardiovascular events, including acute myocardial infarction and stroke, has been correlated with lengthy or high-dose treatment with PPIs [43-44]. Also, there is a concern that theoretical risk of malignant ventricular arrhythmias has been warned due to the development of hypomagnesemia, which may lengthen the QT interval and lead to torsade de pointes [45]. PPI use may lead to reduction of endothelial nitrous oxide levels through inhibition of dimethylarginine dimethylaminohydrolase enzymatic activity, which is responsible for clearance of asymmetric dimethylarginine, thereby reducing nitrous oxide synthase activity [46]. PPIs seem to increase the blood levels of chromogranin A, an important marker of neuroendocrine tumors that investigators have also proposed to be a biomarker of cardiovascular disease [47]. Chromogranin A and its derived peptides, vasostatins and catestatin, elicit vasodilatory and cardioregulatory effects that may be adaptive over the short term and maladaptive over the long term [48]. Finally, PPIs impair clopidogrel's antiplatelet effect due to competition for the cytochrome P450 isoenzyme CYP2C19 [42].
Other adverse effects
Other, less prevalent side effects of PPIs are myopathy [49], hypomagnesemia [45], anemia, fundic gland polyps, micronutrient deficiencies, and subacute cutaneous lupus erythematosus [50].
Conclusions
The risks and benefits of long-term PPI use should be carefully considered, especially in young patients, whose treatment with these drugs could last many years. Although there are multiple reported system-related side effects of these drugs, in most patients with appropriate short-term indications, the benefits of PPIs are likely to outweigh the risks.
Notes
The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.
Footnotes
The authors have declared that no competing interests exist.
References
1. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Freedberg DE, Kim LS, Yang YX. Gastroenterology. 2017;152:706–715. [PubMed] [Google Scholar]
2. Side effects of long‐term proton pump inhibitor use: a review. Haastrup PF, Thompson W, Søndergaard J, Jarbøl DE. Basic Clin Pharmacol Toxicol. 2018;123:114–121. [PubMed] [Google Scholar]
3. Proton pump inhibitors and risk of liver cancer and mortality in patients with chronic liver disease: a systematic review and meta-analysis. Song HJ, Jiang X, Henry L, Nguyen MH, Park H. Eur J Clin Pharmacol. 2020;76:851–866. [PMC free article] [PubMed] [Google Scholar]
4. Adverse effects of proton pump inhibitors—evidence and plausibility. Fossmark R, Martinsen TC, Waldum HL. Int J Mol Sci. 2019;20:5203. [PMC free article] [PubMed] [Google Scholar]
5. Proton-pump inhibitors use, and risk of acute kidney injury: a meta-analysis of observational studies. Yang Y, George KC, Shang WF, Zeng R, Ge SW, Xu G. Drug Des Devel Ther. 2017;11:1291–1299. [PMC free article] [PubMed] [Google Scholar]
6. The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis. Nochaiwong S, Ruengorn C, Awiphan R, et al. Nephrol Dial Transplant. 2018;33:331–342. [PubMed] [Google Scholar]
7. Associations of proton-pump inhibitors and H2 receptor antagonists with chronic kidney disease: a meta-analysis. Wijarnpreecha K, Thongprayoon C, Chesdachai S, Panjawatanana P, Ungprasert P, Cheungpasitporn W. Dig Dis Sci. 2017;62:2821–2827. [PubMed] [Google Scholar]
8. Plasma membrane Na+-H+ antiporter and H+-ATPase in the medullary thick ascending limb of rat kidney. Froissart M, Borensztein P, Houillier P, et al. Am J Physiol Cell Physiol. 1992;262:0. [PubMed] [Google Scholar]
9. Omeprazole, a gastric 'proton pump inhibitor': lack of effect on renal handling of electrolytes and urinary acidification. Howden CW, Reid JL. Eur J Clin Pharmacol. 1984;26:639–640. [PubMed] [Google Scholar]
11. Risk of clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Am J Gastroenterol. 2012;107:1011–1019. [PubMed] [Google Scholar]
12. Continuous proton pump inhibitor therapy and the associated risk of recurrent clostridium difficile infection. McDonald EG, Milligan J, Frenette C, Lee TC. JAMA Intern Med. 2015;175:784–791. [PubMed] [Google Scholar]
13. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. DeVault KR. Yearb Med. 2012;2012:367–368. [Google Scholar]
14. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Howell MD, Novack V, Grgurich P, Soulliard D, Novack L, Pencina M, Talmor D. Arch Intern Med. 2010;170:784–790. [PubMed] [Google Scholar]
15. Long-term use of proton pump inhibitors as a risk factor for various adverse manifestations. Koyyada A. Therapies. 2020 [PubMed] [Google Scholar]
16. Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching. Lee SW, Ha EK, Yeniova AÖ, et al. Gut. 2021;70:76–84. [PubMed] [Google Scholar]
17. Increased risk of COVID-19 among users of proton pump inhibitors. Almario CV, Chey WD, Spiegel BMR. Am J Gastroenterol. 2020;115:1707–1715. [PMC free article] [PubMed] [Google Scholar]
18. Gastric neuroendocrine neoplasms and proton pump inhibitors: fact or coincidence? Cavalcoli F, Zilli A, Conte D, Ciafardini C, Massironi S. Scand J Gastroenterol. 2015;50:1397–1403. [PubMed] [Google Scholar]
19. Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a nationwide population-based cohort study in Sweden. Brusselaers N, Wahlin K, Engstrand L, Lagergren J. BMJ Open. 2017;7:0. [PMC free article] [PubMed] [Google Scholar]
20. The enterochromaffin-like [ECL] cell—central in Gastric physiology and pathology. Waldum HL, Sørdal ØF, Mjønes PG. Int J Mol Sci. 2019;20:2444. [PMC free article] [PubMed] [Google Scholar]
21. Proton pump inhibitors increase risk for hepatic encephalopathy in patients with cirrhosis in a population study. Tsai CF, Chen MH, Wang YP, et al. Gastroenterology. 2017;152:134–141. [PubMed] [Google Scholar]
22. Proton pump inhibitors increase the severity of hepatic encephalopathy in cirrhotic patients. Fasullo M, Rau P, Liu DQ, Holzwanger E, Mathew JP, Guilarte-Walker Y, Szabo G. World J Hepatol. 2019;11:522–530. [PMC free article] [PubMed] [Google Scholar]
23. Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study. Min YW, Lim KS, Min BH, et al. Aliment Pharmacol Ther. 2014;40:695–704. [PubMed] [Google Scholar]
24. Proton pump inhibitor and histamine-2 receptor antagonist use and risk of liver cancer in two population-based studies. Tran KT, McMenamin C, Hicks B, et al. Aliment Pharmacol Ther. 2018;48:55–64. [PubMed] [Google Scholar]
25. Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus. Llorente C, Jepsen P, Inamine T, et al. Nat Commun. 2017;8:837. [PMC free article] [PubMed] [Google Scholar]
26. The gut microbiota and liver disease. Llorente C, Schnabl B. Cell Mol Gastroenterol Hepatol. 2015;1:275–284. [PMC free article] [PubMed] [Google Scholar]
27. Expression and processing of gastrin in hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma. Caplin M, Khan K, Savage K, et al. J Hepatol. 1999;30:519–526. [PubMed] [Google Scholar]
28. Hypergastrinemia is associated with adenocarcinomas in the gastric corpus and shorter patient survival. Fossmark R, Sagatun L, Nordrum IS, Sandvik AK, Waldum HL. APMIS. 2015;123:509–514. [PubMed] [Google Scholar]
29. Assessing compound carcinogenicity in vitro using connectivity mapping. Caiment F, Tsamou M, Jennen D, Kleinjans J. Carcinogenesis. 2014;35:201–207. [PubMed] [Google Scholar]
30. Proton pump inhibitors and fracture risk: a review of current evidence and mechanisms involved. Thong BKS, Ima-Nirwana S, Chin KY. Int J Environ Res Public Health. 2019;16:1571. [PMC free article] [PubMed] [Google Scholar]
31. Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Poly TN, Islam MM, Yang HC, Wu CC, Li YC. Osteoporos Int. 2019;30:103–114. [PubMed] [Google Scholar]
32. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Vestergaard P, Rejnmark L, Mosekilde L. Calcif Tissue Int. 2006;79:76–83. [PubMed] [Google Scholar]
33. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Moayyedi P, Eikelboom JW, Bosch J, et al. Gastroenterology. 2019;157:682–691. [PubMed] [Google Scholar]
34. Long-term proton pump inhibitor use is not associated with changes in bone strength and structure. Targownik LE, Goertzen AL, Luo Y, Leslie WD. Am J Gastroenterol. 2017;112:95–101. [PubMed] [Google Scholar]
35. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Schinke T, Schilling AF, Baranowsky A, et al. Nat Med. 2009;15:674–681. [PubMed] [Google Scholar]
36. Gastrin induces parathyroid hormone-like hormone expression in gastric parietal cells. Al Menhali A, Keeley TM, Demitrack ES, Samuelson LC. Am J Physiol Gastrointest Liver Physiol. 2017;312:0. [PMC free article] [PubMed] [Google Scholar]
37. Omeprazole, a specific inhibitor of H+−K+-ATPase, inhibits bone resorptionin vitro. Tuukkanen J, Väänänen HK. Calcif Tissue Int. 1986;38:123–125. [PubMed] [Google Scholar]
38. Proton pump inhibitors and dementia: physiopathological mechanisms and clinical consequences. Ortiz-Guerrero G, Amador-Muñoz D, Calderón-Ospina CA, López-Fuentes D, Mesa MON. Neural Plast. 2018 [PMC free article] [PubMed] [Google Scholar]
39. Omeprazole-induced hallucinations. Not as rare as you might think. Sebastián DJJ. Gastroenterol Hepatol. 2018;41:266–267. [PubMed] [Google Scholar]
40. The proton-pump inhibitor lansoprazole enhances amyloid beta production. Badiola N, Alcalde V, Pujol A, et al. PLoS One. 2013;8:1–8. [PMC free article] [PubMed] [Google Scholar]
41. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. Bloom GS. JAMA Neurol. 2014;71:505–508. [PubMed] [Google Scholar]
42. Proton pump inhibitors and cardiovascular adverse effects: real or surreal worries? Manolis AA, Manolis TA, Melita H, Katsiki N, Manolis AS. Eur J Intern Med. 2020;72:15–26. [PubMed] [Google Scholar]
43. Long-term use of proton pump inhibitors, dose-response relationship and associated risk of ischemic stroke and myocardial infarction. Sehested TSG, Gerds TA, Fosbøl EL, et al. J Intern Med. 2018;283:268–281. [PubMed] [Google Scholar]
44. Use of proton pump inhibitors and risk of ischemic events in the general population. Casula M, Scotti L, Galimberti F, Mozzanica F, Tragni E, Corrao G, Catapano AL. Atherosclerosis. 2018;277:123–129. [PubMed] [Google Scholar]
45. Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies. Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, et al. Ren Fail. 2015;37:1237–1241. [PubMed] [Google Scholar]
46. Endothelins in cardiovascular biology and therapeutics. Dhaun N, Webb DJ. Nat Rev Cardiol. 2019;16:491–502. [PubMed] [Google Scholar]
47. Chromogranin A as a biomarker in cardiovascular disease. Goetze JP, Alehagen U, Flyvbjerg A, Rehfeld JF. Biomark Med. 2014;8:133–140. [PubMed] [Google Scholar]
48. Biological function and clinical relevance of chromogranin A and derived peptides. D'amico MA, Ghinassi B, Izzicupo P, Manzoli L, Di Baldassarre A. Endocr Connect. 2014;3:0. [PMC free article] [PubMed] [Google Scholar]
49. Proton pump inhibitors: risk for myopathy? Colmenares EW, Pappas AL. Ann Pharmacother. 2017;51:66–71. [PubMed] [Google Scholar]
50. Complications of proton pump inhibitor therapy. Vaezi MF, Yang YX, Howden CW. Gastroenterology. 2017;153:35–48. [PubMed] [Google Scholar]
Articles from Cureus are provided here courtesy of Cureus Inc.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887997/