Proton pump inhibitors: Risks of long-term use

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1 bs_bs_banner doi: /jgh REVIEW Proton pump inhibitors: Risks of long-term use Leonardo Henry Eusebi,*, Stefano Rabitti,* Maria Laura Artesiani,* Dania Gelli,* Marco Montagnani,* Rocco Maurizio Zagari* and Franco Bazzoli* *Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Gastroenterology and Endoscopy Unit, Sant Orsola University Hospital, Bologna, Italy; and HPB Diseases, Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive Health, London, UK Key words complications, long-term risk, proton pump inhibitor. Accepted for publication 12 January Correspondence Dr Leonardo Henry Eusebi, Department of Medical and Surgical Sciences, University of Bologna, Gastroenterology and Endoscopy Unit, Sant Orsola University Hospital, Via Massarenti 9, 40138, Bologna, Italy. Abstract Proton pump inhibitors are among the most commonly prescribed classes of drugs, and their use is increasing, in particular for long-term treatment, often being over-prescribed and used for inappropriate conditions. In recent years, considerable attention has been directed towards a wide range of adverse effects, and even when a potential underlying biological mechanism is plausible, the clinical evidence of the adverse effect is often weak. Several long-term side effects have been investigated ranging from interaction with other drugs, increased risk of infection, reduced intestinal absorption of vitamins and minerals, and more recently kidney damage and dementia. The most recent literature regarding these adverse effects and their association with long-term proton pump inhibitor treatment is reviewed, and the mechanisms through which these possible complications might develop are discussed. Disclosure statement: All Authors have no conflict of interest and declare that no funds were received for this paper. Introduction Proton pump inhibitors (PPIs) are among the most commonly prescribed classes of drugs, widely used to treat patients with acidrelated disorders, such as gastroesophageal reflux disease and peptic ulcer. Their use is increasing, particularly for long-term treatment, often being over-prescribed and used for inappropriate conditions. 1 PPIs are generally considered to be effective and well tolerated, with only rare and mild side effects in short-term use PPIs, whereas concern and evidence on the potential long-term complications of PPI therapy are increasingly emerging. The potential adverse effects range from interaction with other drugs, increased risk of infections, reduced intestinal absorption of vitamins and minerals, and more recently kidney damage and dementia, investigated mainly by case control and cohort studies. We have reviewed the most recent literature reporting possible associations between long-term PPI treatment and adverse effects and discussed the mechanisms through which these complications might develop (Table 1). Vitamins and minerals absorption The gastric acid environment plays a major role in the physiologic pathways although which most micronutrients and drugs are digested and absorbed. Changes related to long-term gastric acid inhibition may interfere in particular with the absorption of several vitamins and minerals. Dietary iron is mostly constituted by non-haem iron in ferric form (Fe3+) that is poorly soluble above a ph of 3. Thus, ferric iron needs to be oxidized to more soluble forms (ferrous, Fe2+) for a better absorption in the duodenum. This process appears to be facilitated by gastric juice; in particular, the interaction between Vitamin C released in gastric secretion and iron compounds seems to promote the formation of a more absorbable ferric form. 12 As PPIs low gastric acid levels, a possible interaction between PPI therapy and iron absorption has been proposed. A retrospective cohort study reported a significant association between the chronic use of PPI and the presence of anemia, showing a decrease of most haematological values in PPI users 13 ; however, a small sample size and presence of potential confounders could have influenced the validity of the results. The reduction in absorption of non-heme iron associated with the use of PPIs has been reported also in patients affected by haemochromatosis, reducing the number of phlebotomies needed per year. 14 Despite these intriguing data, the evidence of a correlation between PPI assumption and the development of iron deficit anemia remains poor and mainly based on case reports or small observational studies. Thus, routine investigation of anemia in patients on long-term PPI treatment is not recommended in clinical practice, although association between long-term PPI treatment and anemia should be considered after excluding all other main causes. B12 is a protein-bound vitamin introduced mainly through dairy products and meat that requires the presence of gastric acid and pepsin to be liberated in the stomach. It subsequently binds to R factors forming a non-absorbable complex present in saliva and gastric juice. In the duodenum, the alkaline pancreatic juice that contains proteases brakes up the binding between B12 and R factor allowing the cobalamine to bind with the intrinsic factor, a necessary step for it to be absorbed in terminal ileum. 15 Taking into account this complex sequence Journal of Gastroenterology and Hepatology 32 (2017)

2 Proton pump inhibitors LH Eusebi et al. Table 1 Potential adverse effects of long term PPI treatment Potential adverse effect Quality of evidence Strength of association Plausible underlying biological mechanism Risk of fracture Hypomagnesaemia Randomized trials, observational studies, systematic review and meta-analysis Systematic review and meta-analysis of observational studies Weak, OR < 2 2,3 Weak, OR < 2 4 Reduced calcium absorption in the duodenum and proximal jejunum as a consequence of achloridria Poorly defined (gastrointestinal malabsorption and renal wasting) Vitamin B12 deficiency Observational studies Weak Reduced acid-activated proteolytic digestion in the stomach related to reduced absorption Dementia Observational studies Uncertain High levels of amyloid-β and deposition of amyloid-β peptides in brains of animal models Cardiovascular risk Meta-analysis of observational studies and of RCT Weak, OR < 2 for mortality and myocardial infarction (not significant when only RCT were included) 5 Competitive metabolism effect on cytochrome P450 Renal disease Observational studies Modest Unclear (deposit of PPIs or their metabolites in the kidney s tubulointerstitium stimulating immune response) C. difficile infection Meta-analysis of observational studies Weak, OR < Reduce gastric acidity may promote bacterial colonization in the GI tract Pneumonia Meta-analysis of observational studies, case control studies Weak, OR < 2 9 Potential micro-aspiration or translocation into the lungs from upper GI bacterial overgrowth Fundic gland polyps Observational studies Consistent Trophic effect of high gastrin levels on GI mucosa Gastric cancer Meta-analysis of observational studies Uncertain, OR < 2 for gastric cancer, not significant for pre-neoplastic lesion 10,11 Possible synergic effect of PPI treatment and Helicobacter pylori infection Colon cancer Observational studies No clear clinical association Trophic effect of high gastrin levels on colon cancer cells in vitro GI, gastrointestinal; OR, odds ratio; PPI, proton pump inhibitor; RCT, randomized clinical trial. of events, the decrease of gastric acid production induced by PPI could hypothetically lead to vitamin B12 malabsorption. However, conflicting results regarding the association have been reported. In a recent large case control study conducted in a community-based setting, patients having incident diagnosis of vitamin B12 deficit were compared with patients without B12 deficit. Results showed that the use of PPIs for 2 years or more was significantly associated with a new diagnosis of vitamin B12 deficiency. A stronger association was found for woman and younger patients, and the risk decreased after suspension of PPI treatment. 16 In contrast, a recent cross-sectional study failed to demonstrate a significant difference between vitamin B12 serum levels in 125 long-term PPI consumers compared with their partners not on PPIs. 17 A decrease in the absorption of protein-bound vitamin B12 in association with PPIs use has also been reported; however, Schenk and Colleagues found that such decrease is not always correlated to low vitamin B12 serum levels. 18 Although several studies seem to suggest that long-term use of PPI could cause vitamin B12 malabsorption promoting vitamin B12 deficiency, data are still conflicting, and further studies focusing on the effect of long-term PPI treatment on vitamin B12 metabolism are needed. Hypomagnesaemia was first described as a complication of PPIs treatment in Since then, many other cases have been reported, and in 2011, the US Food and Drug Administration released a warning about low serum magnesium levels associated with long-term PPI use. 20 Moreover, the results of a recent systematic review 21 and of a meta-analysis of nine observational studies 4 suggest that in case of low magnesium serum levels, PPI treatment should be discontinued. Several clinical manifestations of hypomagnesaemia have been reported, including gastrointestinal (GI) symptoms, depression, tremor, paraesthesia, seizures, tetany, and ataxia, although only rarely requiring inpatient management. Prompt resolution of hypomagnesaemia after 1 to 2 weeks from PPI withdrawal and the recurrence after PPI re-challenge suggest a possible direct interaction between this class of drugs and magnesium metabolism. The underlying mechanisms remain poorly defined. GI malabsorption and renal wasting have been proposed, but evidence-based studies are required to better define the biological mechanism behind this association Journal of Gastroenterology and Hepatology 32 (2017)

3 LH Eusebi et al. Proton pump inhibitors Calcium absorption and bone fracture risk. Dietary calcium is absorbed throughout the whole gut by paracellular transport and also by a transcellular pathway via the transient receptor potential vailloid 6 channel at the level of the apical membrane of the duodenum and proximal jejunum. However, the absorption of calcium compounds can be significantly reduced in the presence of achlorhydria, 22 linking PPIs as a potential causal agent for calcium malabsorption. Indeed, a randomized cross-over trial on women older than 65 years of age showed a significant reduction of calcium carbonate absorption in omeprazole users. 23 On the contrary, a study performed on young male patients did not find any significant difference between the absorption of dietary calcium among patients taking full dose of omeprazole compared with controls. 24 This discrepancy of results could be related to the different methodologies used and to the better absorption of dietary calcium compared with the supplemented one. 25 The effects of PPI on calcium metabolism have also been correlated to a higher incidence of bone fractures. The mechanisms behind this association are complex and multifactorial. As previously mentioned, long-term use of PPIs could lead to vitamin B12 malabsorption that increases homocysteine levels and reduces the osteoblastic activity with subsequent effects on bone formation and strength. Moreover, the hypergastrinemia secondary to prolonged acid suppression, together with a diminished calcium absorption, triggers the production of parathormone stimulating bone resorption. 26 In the systematic review by Ngamruengphong and coworkers, only a modest association between PPI use and increased risk of hip and vertebral fractures was reported. However, the Authors suggest caution in the interpretation of their results because no evidence of duration effect was found in the subgroup analysis, and possible confounding factors could have affected the results. 2 A more recent meta-analysis of 18 observational studies, including a total of fractures, reported a higher risk of hip fractures, spine fractures, and for fractures at any site not only after longterm treatment but also in case of PPIs use for less than 1 year. 3 In conclusion, the evidence suggests caution when prescribing long-term PPI treatments in patients with increased risk of bone fractures. Moreover, in case of postmenopausal women on long-term therapy with PPIs, it is recommended to increase dietary calcium intake and, if necessary, prefer calcium supplements that are not influenced by gastric acid for absorption, such as calcium citrate. 27 Dementia The hypothesis that the use of PPIs, especially in elderly patients, can be associated with an increased risk of dementia has been formulated based on the effect of PPIs on amyloid metabolism in animal models. Indeed, PPI treatments enhance the production of amyloid-β and modulate its degradation by lysosomes in microglia. 28 This leads to higher levels of amyloid-β in brains of mice, similar to the extracellular deposition of amyloid-β peptides seen in the pathogenesis of Alzheimer s disease. Moreover, low vitamin B12 status has been associated with cognitive deficit highlighting a possible role of vitamins malabsorption due to long-time PPI treatment as reported in the previous paragraph. Only limited number of studies have investigated this association in humans. Haenisch and colleagues, using data from a longitudinal multicentre cohort study, assessed the association between PPI use and risk of dementia in elderly subjects. They found that patients receiving PPIs had a significantly increased risk of any dementia and of Alzheimer s disease compared with subjects not receiving PPI medication. 29 Moreover, Authors from the same research group found similar results in a large prospective cohort study analyzing observational data from participants of 75 years of age or older, confirming that patients receiving PPI treatment had a significantly increased risk of dementia compared with nonusers. 30 More studies, and in particular randomized clinical trials (RCTs), are needed to confirm this association, and to establish whether reducing PPIs use in the elderly may prevent the development of dementia. Alteration of clopidogrel pharmacodynamics and cardiovascular risk Patients on antiplatelet therapy following acute coronary syndromes and percutaneous coronary interventions are often also prescribed PPIs to prevent GI complications. However, based on in vitro pharmacokinetic platelet aggregation studies, concerns about a potential interaction between PPIs and clopidogrel, leading to an attenuated antiplatelet effect caused by PPIs, have been raised. Indeed, a competitive metabolism effect has been suggested because PPIs are metabolized by the cytochrome P450, in particular CYP2C19 and CYP3A4, which are also involved in the biotransformation of clopidogrel to an active form. These findings led the FDA in 2009 to warn against combining clopidogrel and PPIs, in particular against potent CYP2C19 inhibitors, naming mainly omeprazole. 31 Shah and colleagues found a small but significant 1.16-fold increased association between myocardial infarction and use of PPIs among patients with gastroesophageal reflux, as well as a twofold increase in association with cardiovascular mortality. Interestingly, the Authors found that this association was present regardless of clopidogrel use. 32 Two recent meta-analyses have confirmed that patients using PPIs with clopidogrel have an increased risk of cardiovascular events, including higher overall mortality, myocardial infarction, and acute coronary syndromes, compared with nonusers when non-randomized observational studies are pooled together. However, conflicting results were found when only RCTs were included; no significant differences in ischemic events or mortality were observed in RCTs, while the use of PPIs in patients taking clopidogrel was significantly associated with a reduced risk of GI bleeding. 5,33 Selection bias and confounders in the observational studies are the most likely to explain the discordant findings with RTCs. These results seem to suggest that PPIs are a marker of increased risk rather than a direct cause of worse outcome, and further studies examining the issue are needed to clarify this important issue. 21 Therefore, to reduce competitive metabolism with clopidogrel, first of all, PPIs with a reduced interaction with CYP2C19 enzyme (e.g. Esomeprazole or Pantoprazole) should be chosen. As an Journal of Gastroenterology and Hepatology 32 (2017)

4 Proton pump inhibitors LH Eusebi et al. alternative, H2-receptor antagonists can be used to suppress gastric acid production, or the next-generation antiplatelet agents not dependent on the CYP2C19 enzyme, such as ticagrelor or prasugrel, could be used to substitute clopidogrel. The option of a temporal separation of the administration of dosing does not appear to prevent drug interactions between PPI and clopidogrel, not even by a 12-h apart administration. 34 Finally, a novel potassium-competitive acid blocker has been developed to resolve the limitations of conventional PPIs. Initial clinical trials have been very encouraging; however, long-term efficacy and possible side effects need still to be evaluated. 35 Renal disease Proton pump inhibitors have been increasingly suspected of causing renal damage, particularly among older patients. Indeed, acute interstitial nephritis (AIN) is the most frequently observed acute kidney damage in PPI users. 36 During recent years, three large population-based studies, performed in Canada, United States, and New Zealand, reported a higher risk of AIN and acute kidney injury in patients prescribed with PPIs In the Canadian study that included more than individuals older than 66 years on PPI therapy and an equal number of controls, the risk of acute renal disease and AIN was 2.5- and 3-fold higher, respectively, in PPI users compared with controls. 37 Similarly, in the population-based nested case cohort study from the USA that included subjects 18 years or older, acute kidney injury was twofold more common in patients who had used PPIs compared with those who had not, and results were similar after controlling for multiple potential confounding variables. 38 In the New Zealand study, of patients without a history of kidney disease, the risk of AIN was fivefold higher for current PPI users compared with the entire cohort. Moreover, current users of PPIs had higher incidence of acute kidney injury also compared with past PPI users. 39 The specific mechanism by which PPIs lead to AIN is still unknown. As it occurs with other drug-induced kidney diseases, it is conceivable that PPIs or their metabolites might deposit in the kidney s tubulo-interstitium compartment and directly stimulate an immune response leading to AIN. Moreover, recent data have also highlighted the possible association between long-term PPI treatment and induced chronic kidney disease (CKD). Indeed, the long-standing lower glomerular filtration rate due to PPIinduced AIN may transition to chronic interstitial nephritis leading to higher CKD risk on a longer-term follow-up. 21,36 In the study by Lazarus and colleagues, the risk of CKD in participants was 50% higher in PPI users compared with nonusers. Moreover, the Authors also reported a dose response effect showing a higher risk among patients taking PPIs twice daily compared with once a day, and a higher risk compared with patients taking histamine H2 antagonists. 40 A second study by Arora and coworkers evaluated in veterans the association between PPI use and chronic renal disease, from 2001 to 2008, finding that among 34% veterans who developed CKD during the study, those using PPIs had a significantly higher risk of CKD development. 41 A similar study by Xie and colleagues used national veterans database to identify new users of PPI and followed them for 5 years to evaluate the risk of renal disease. The Authors found that patients treated with PPIs also had a significantly increased risk of CKD and a doubling of serum creatinine level. 42 Therefore, caution should be used when prescribing PPIs to older subjects especially if they present with other risk factors for renal disease, suggesting to monitor renal function in these patients during long-term treatment. Infections Gastric acid secretion plays a pivotal role in the digestive process also as part of the local defensive system against orally ingested pathogens. In this context, the reduced acid secretion induced by PPIs could alter the composition of the GI flora and may facilitate bacterial ascending colonization from distal to proximal intestinal tracts. Thus, the changes in the intestinal microflora represent a plausible biological explanation for increased susceptibility to GI infections during PPI therapy. 43 Enteric infections. Most studies have investigated the possible association between proton-pump inhibitors and Clostridium difficile infection (CDI), because PPIs are assumed to increase the proliferation of spores by decreasing the intraluminal gastric acidity, allowing spores to survive in the modified gastric environment. 44 However, it is unlikely that the association of CDI with the PPI is simply due to a transgastric resistance of the spores ingested, but rather to a better spread of CDI due to a modified microbiota induced by the PPI treatment. Although few studies did not detect changes in the relative abundance of specific organisms, 45 a recent large study aimed to investigate the influence of PPI use on the gut microbiome from 1815 individuals observed persistent changes towards a less healthy gut microbiome among PPI users compared with nonusers. Moreover, these changes were in line with known alterations that predispose to CDI, potentially explaining the increased risk of enteric infections in PPI users. 46 In 2012, three meta-analyses evaluated the association between PPI use and CDI. 6 8 Kwok and colleagues analyzed data from 39 studies that showed a significant association between PPI use and the risk of CDI, with an odds ratio (OR) of 1.74 (95% confidence interval (CI) , P < 0.001) compared with non- PPI users. The Authors also considered the association between PPIs and antibiotics and found that the risk of CDI was increased further in cases of concomitant use of the two drugs. 6 Similar results were found by Tleyjeh and coworkers including 47 eligible studies: 37 case control and 14 cohort studies, where the pooled OR was 1.65 (95% CI ). 8 Although statistically significant association between PPI use and the risk of CDI was found in both meta-analyses, high heterogeneity among studies and publication bias weakened the results. Nevertheless, these findings warrant careful use of PPIs in patients at higher risk for CDI development, such as people with known risk factors for infection including advanced age, undergoing chemotherapy, immunodeficiency, and exposure to infected subjects. In addition to C. difficile-associated disease, it has been postulated that strong suppression of acid could also increase the risk of other enteric infections. Indeed, an increased risk for both Salmonella and Campylobacter infections has been reported in PPI users. 47 Brophy and coworkers used a general practitioner database to evaluate the incidence of these infections following a PPI 1298 Journal of Gastroenterology and Hepatology 32 (2017)

5 LH Eusebi et al. Proton pump inhibitors prescription among people. The PPI group had an increased risk of infection for Campylobacter (HR 1.46) and for Salmonella (HR 1.2) compared with baseline. However, patients prescribed a PPI had a higher rate of enteric infection even before receiving PPI treatment, leading the Authors to conclude that the association was more likely due to inherent factors within the patient than related to the PPI prescription. 48 The use of PPIs might also predispose to small intestinal bacterial overgrowth (SIBO). Lo and Chan analyzed eleven studies, comparing SIBO risk among adult PPIs users vs nonusers. 49 The Authors found a significant association between PPI use and SIBO, but only in studies in which SIBO diagnosis was made by duodenal/jejunal aspirate culture. Several mechanism of pathogenesis have been described, including reduced bacterial clearance, intestinal bacterial overgrowth, altered GI motility, and increased intestinal permeability 44 ; nevertheless, further studies are needed to define the diagnostic modalities for SIBO and to assess their specific impact on the clinical outcome. PPIs lead to a significant change in the overall microbiota composition also in patients with cirrhosis. 50 Indeed, SIBO is also considered a predisposing factor for spontaneous bacterial peritonitis, a condition that can complicate by up to 30% the clinical course in cirrhotic patients with ascites. 44 Recent studies have shown possible PPI-related complications in cirrhotic patients, 51 like SIBO and infectious complications. 52 In particular, in the meta-analysis by Deshpande and colleagues from eight observational studies, a threefold higher risk of developing spontaneous bacterial peritonitis among patients taking PPIs was found compared with the nonreceivers. 53 A prospective study that investigated the relationship between PPI treatment and the overall survival in cirrhotic patients, including 272 patients, 213 of whom were on PPI treatment, reported that PPI treatment was associated with higher Model for End- Stage Liver Disease (MELD) scores and presence of ascites. Furthermore, PPI treatment was also significantly associated with increased mortality and was considered the second cause of death in cirrhotic patients, after presence of hepatocarcinoma, 54 further confirming that PPIs should be used with caution in these complex patients with advanced liver disease. Pneumonia. Several studies examined the potential risk of community-acquired pneumonia (CAP) among subjects treated with PPIs. Upper GI bacterial overgrowth, a possible consequence of long-term PPI treatment, may lead to an increased susceptibility to respiratory infections by potential micro-aspiration or translocation into the lungs. 55 This association seems biologically plausible, even although the studies were residual and somehow confounding. In fact, the clinical relevance of the association is probably scarcely significant. A recent large meta-analysis included cases of CAP among participants from 26 studies. Although there was a strong heterogeneity among studies, a significant risk of CAP related to PPI therapy was found (OR 1.49; 95% CI ), and the risk raised during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16) regardless of PPI dose or patient age. Moreover, PPI therapy also increased the risk for hospitalization for CAP (OR 1.61; 95%CI ). 9 On the other hand, Dublin and colleagues conducted a population-based case control study among more than 3300 adults aged years with CAP and did not find a significant association with current PPI therapy compared with controls (21% vs 16%). 56 Similarly, an older case control study did not find an increased risk of CAP associated also with the prolonged use of PPI. 57 Therefore, at present, the epidemiologic evidence on the association between PPI therapy and CAP is still controversial, and further studies should specifically address this issue. Proton pump inhibitors and gastrointestinal neoplasia In animal models, the carcinogenicity of PPIs has been widely studied, especially in rodents where PPIs have been shown to cause cancer and other rare GI tumors. In humans, this association is less evident; nevertheless, major concerns about the use of longterm PPI and the development of GI cancers, in particular, gastric and colon cancer and carcinoid tumor, have been raised. 58 Gastric polyps. The most common gastric polyps are the fundic gland polyps (FGPs) that are divided into two subtypes: the sporadic polyps, which are found in nearly 2% of the general population, and the syndromic FGPs, which are present in more than 80% of patients with familial adenomatous polyposis. In their large case control study, Jalving and coworkers included 600 patients evaluating data about the use of PPIs before undergoing endoscopy and the presence of FGPs. Long-term PPI use was significantly associated with a twofold increased risk of FGPs in case of 1 to 5 years use of PPIs and a fourfold risk for treatment lasting more than 5 years. On the other hand, short-term therapy (< 1 year) was not significantly associated with the presence of FGPs. Therefore, the risk of sporadic FGPs seems to increase with long-term use of PPIs, and it continues to increase with a prolonged use, whereas short-term treatment does not seem to be related with an increased risk of FGPs development. 59 Indeed, Tran-Duy and coworkers, in their recent meta-analysis, confirmed that at least 12 months of continued PPI use is a necessary condition for the development of FGPs, although the clinical significance of these polyps remains unclear. 60 A prospective study performed by Zelter and colleagues in nearly 1800 endoscopies reported 77 patients with FGPs (64%), and 49 of these were taking PPIs. The Authors concluded that PPI treatment is one of the strongest risk factors for the development of FGPs, and their high prevalence is probably due to the increased prescription in recent years, but no evidence of dysplasia or sporadic cancer has been observed. 61 Evidence of malignant transformation was also not found by Genta and coworkers using data from more than 6000 patients with FGPs. 62 Therefore, the evolution of FGPs towards dysplasia seems to be an extremely rare event, and endoscopic follow-up for these polyps is not currently suggested. On the contrary, the syndromic FGPs associated with familial adenomatous polyposis seem to have a major risk of dysplasia suggesting an endoscopic surveillance in these patients. 59 Gastric cancer. Several recent studies tried to define a correlation between chronic PPIs use and the development of gastric cancer (GC). Among these, a large observational study analyzing data from a Dutch database containing the records of nearly Journal of Gastroenterology and Hepatology 32 (2017)

6 Proton pump inhibitors LH Eusebi et al PPI users has shown that, after 8 years of follow up, 45 (0.16%) patients were diagnosed with gastric cancer compared with 22 (0.01%) cases among the control subjects not using PPIs. The difference among the groups was significant, thus easily interpreted as an increased risk among the PPI users; however, a possible prothopatic bias (a cancerous lesion could have been already present before PPIs were prescribed) could not be excluded by the Authors. 63 An increased incidence of gastric cancer associated with PPI use was also observed in a similar study from Denmark. The Danish National Health-Care System was investigated to evaluate the incidence of gastric cancer among PPI new users between 1990 and The Authors found an incidence rate ratio of 1.2, and although Helicobacter pylori infection and a confounding by indication bias may be an explanation, the possibility of a causal association between long-term PPI use and risk of gastric cancer cannot be ignored. 64 H. pylori infection, besides being a well-established risk factor for GC, is known to cause a loss of parietal cells and therefore a reduction of gastric secretion. 65 The consequential hypochlorhydria could increase the risk of bacterial overgrowth responsible for the worsening gastritis observed in patients with H. pylori infection undergoing treatment with PPI. Moreover, gastric atrophy and hypochlorhydria could lead to non-helicobacter microbiota overgrowth that may increase the risk of developing GC in H. pylori infected patients. 66 A subgroup analysis performed by Tran-Duy and coworkers has added information about the duration of the PPI therapy, reporting that after a long lasting treatment with PPI (> 36 months), the interaction between H. pylori infection and PPI use can cause a more severe gastritis than shorter treatment periods, leading to an increased risk of atrophic gastritis. 60 A meta-analysis of 11 observational studies reported that the use of acid suppressive drugs was associated with an increased risk of gastric cancer, although the lack of information on H. pylori infection limits the results. 10 In contrast, a systematic review performed by Song and colleagues showed a non-significant difference between PPI users and nonusers for presence of gastric preneoplastic lesions, such as corpus atrophy or intestinal metaplasia. 11 A more recent FDA-mandated long-term follow-up study by Schneider and coworkers found no evidence of an increased risk of gastric cancer, of other GI cancers or of any cancer for pantoprazole, a longer-acting PPI, compared with other PPIs. 58 In conclusion, there is no clear evidence that PPIs increase the risk of gastric cancer; however, in the presence of corpus predominant gastritis and atrophy in subjects infected by H. pylori, according to the Maastricht guidelines, eradication treatment is recommended before starting long-term PPI therapy in order to prevent the progression to atrophic gastritis. 67 Gastric carcinoids. Another important area of concern is the effect of long-term PPI treatment and of the consequent hypergastrinaemia on the enterochromaffin-like (ECL) cells and the possible development of preneoplastic and carcinoid lesions. 58 Brunner and coworkers studied the effects of daily pantoprazole therapy for up to 15 years and showed no evidence that in humans, hypergastrinaemia leads to dysplastic or neoplastic ECL cell changes, whereas in rats, the development of gastric carcinoids reached up to 30%. 68 Similarly, Lundell and colleagues have indicated that long-term PPI use is associated only with moderate hypergastrinaemia resulting in an increased prevalence of ECL cell hyperplasia; however, none of the patients included in the study developed a neuroendocrine tumor (NET). The development of neuroendocrine tumor in patients using long-term treatment with PPI is an unclear and rare event as it has only been documented by few case reports, and therefore, these findings could be coincidental. 69,70 The progression towards dysplasia has only been reported in rare cases of Zollinger Ellison syndrome and multiple endocrine neoplasia type I, but this was due to marked hypergastrinaemia and presence of chronic atrophic gastritis, rather than to PPI treatment. 68 Nevertheless, long-term PPI can be used easier in older subject as the transformation from hyperplasia to carcinoma is a slow process, whereas H-2 blockers could be preferably used to treat gastroesophageal reflux disease and esophagitis symptoms in younger patients. Alternatively, the combination of PPI and a gastrin antagonist (netazepide) has also been reported to decrease the development of ECL cell tumors. 71 Colon cancer. Gastrin has been found to be involved in tumorigenesis in the GI tract, and it has been demonstrated that high gastrin levels have a trophic effect also on colon cancer cells in vitro; thus theoretically, hypergastrinaemia could lead to development of colonic adenoma and colorectal cancer (CRC). 72 Three large case control studies have been conducted to evaluate this association in humans. A UK general practice research database study, based on more than 4400 CRC cases and controls, proved that long-term PPI therapy at a regular dose was not associated with a significantly increased risk of CRC for > 5 years of PPI exposure. 73 Similarly, the other two studies, one from Denmark and one from the Nederlands, also showed no evidence of increased risk of CRC in long-term PPI users. 74,75 The lack of an association between PPI therapy and CRC risk might be due to the mechanism of action of PPIs that increase the production of fully processed amidated gastrin, which together with modest hypergastrinemia seem to have only a weak effect on colorectal epithelium. Conclusions Proton pump inhibitors are among the safest and most effective drugs; however, in recent years, considerable attention has been pointed towards a wide range of adverse effects. The majority of the observed associations are mainly based on observational studies, and confounding factors and alternative possible explanations need to be taken in account when evaluating these studies. In most cases, RCT would be useful to further confirm these associations although complex to perform. For most side effects, a clear underlying biological mechanism is plausible; however, the clinical evidence of the adverse effect is often weak and cannot be clearly associated to PPIs use. In particular, while short-term PPI treatment rarely represents any harm, more concerns for complications regarding long-term prescriptions and special attention should be given to elderly patients with 1300 Journal of Gastroenterology and Hepatology 32 (2017)

7 LH Eusebi et al. Proton pump inhibitors significant comorbidity and on multidrug treatment when starting PPIs therapy. Finally, in most cases and based on the available evidence, PPIs benefits seem to outweigh potential adverse effects. Nevertheless, PPIs are frequently overprescribed in many patients, and the clinical indications should always be reviewed to determine whether the treatment is still necessary. References 1 Johnson DA, Oldfield EC. Reported side effects and complications of long-term proton pump inhibitor use: dissecting the evidence. Clin. Gastroenterol. Hepatol. 2013; 11: ; quiz e Ngamruengphong S, Leontiadis GI, Radhi S, Dentino A, Nugent K. Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am. J. Gastroenterol. 2011; 106: ; quiz Zhou B, Huang Y, Li H, Sun W, Liu J. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos. 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