REPEAT FOREVER: ARE PPIs BENIGN?
Z A KHAN
MBChB, FCS, Cert Gastro (SA)
Surgical gastroenterologist. Department of Surgery, University of the Witwatersrand and Chris Hani Baragwanath Academic Hospital
Proton Pump Inhibitors (PPI) have changed the landscape in the management of peptic ulcer and Gastro-Oesophageal Reflux Disease (GORD). However, in recent years several epidemiologic studies have demonstrated significant adverse events associated with their use. Furthermore, PPIs are often prescribed in the absence of a sound indication. This has sparked a media uproar leading to several drug control bodies issuing cautionary warnings on PPI use.
PPIs have a 1-3% risk of side effects, most commonly headaches, nausea, dizziness, flatulence, abdominal pain, rash, diarrhea and constipation1. In general, adverse events attributed to PPI use include: kidney dysfunction, malabsorption (iron, folate, vitamin B12, calcium, and magnesium), gastric changes, infections (respiratory tract, small intestinal bacterial overgrowth, and enteric/colonic infections), drug interactions and cognitive decline.
A comprehensive review of all adverse events is beyond the scope of this paper. This paper will focus on the most prominent associations. These are summarised in Table 15.
Table 1: Adapted from Abraham NS. Curr Opin Gastroen 2012 Potential PPI adverse effects Biologically plausible mechanism Strength of association Consistency of association Recommendation Acute interstitial nephritis Interaction biologically plausible Higher magnitude (Ratio >2)
Inconsistent High index of suspicion if symptoms develop Hypomagnesaemia Interaction biologically plausible Low magnitude (Ratio <2)
Inconsistent Consider monitoring if additional risk factors present
Iron deficiency Interaction biologically plausible Low magnitude (Ratio < 2) Inconsistent No screening B12 deficiency Interaction biologically plausible Low magnitude (Ratio <2)
Inconsistent Consider screening when additional risk factors present
Gastric tumours Interaction biologically plausible
Low magnitude (Ratio <2)
Inconsistent Eradicate patients with H pylori
Bone fractures Interaction biologically plausible
Low magnitude (Ratio <2)
Inconsistent No screening
Respiratory infection Interaction biologically plausible
Low magnitude ratio (<2)
Inconsistent Do not withhold PPI if appropriate
Clopidogrel interaction Interaction biologically plausible
Low magnitude (Ratio <2)
Inconsistent Do not withhold PPI if appropriate
Enteric infections Interaction biologically plausible
Higher magnitude (Ratio >2)
Inconsistent Weigh risk benefit. Consider stopping if no urgent indication and presence of diarrhea
Acute Interstitial Nephritis (AIN)
Mechanism: Incompletely understood. It is thought to be a Type B idiosyncratic non-immunoglobulin E mediated immune reaction characterised by cell mediated immune injury to the cells of the renal tubulointerstitium. This is as a result of the drug becoming immunogenic through various mechanisms (haptenization, antigen mimicry, and neo-antigen formation)2.
Evidence: The first systematic review in 2007 of PPI-related AIN found only 64 cases consisting of case series and case reports3. It was concluded that the association was rare and idiosyncratic and thus difficult to predict.
Furthermore, it was impossible to establish causality with certainty due to the small sample size but there did appear to be a low prevalence association.
In a large nested cohort study from New Zealand of 572 661 patients, 46 definite and 26 probable cases were defined4. The crude absolute risk after adjusting for confounders was 11.98 and 1.68 per 100 000 person years for current and past use respectively. This effect was most pronounced in the elderly4. Two recent series of patients with drug induced interstitial nephritis found PPIs to be the cause in approximately 15% of cases5,6.
Conclusion: Although there appears to be an association between PPIs and AIN, there is limited data. Observational studies do not adequately control for confounding factors. Care should be taken when used in elderly patients. Given its rare and idiosyncratic nature, diagnosis requires a high index of suspicion.
CHRONIC KIDNEY DISEASE
Mechanism: Unknown.
Evidence: Two recent observational studies have described an increased incidence of chronic kidney disease in patients taking PPIs7,8. Lazarus found that twice daily dosing increased the risk of injury with Xie also demonstrating an association between duration of PPI exposure and kidney injury7,8.
Conclusion: Limited data. Further studies are required to prove a causal relationship between PPI and chronic kidney injury.
GASTRIC TUMOURS
Mechanism: PPIs cause an increase in gastric pH with an increase in gastrin secretion. Gastrin exerts a trophic effect on EnteroChromaffin cells (ECL) of the stomach resulting in hyperplasia.
In early animal testing of omeprazole several rats developed carcinoid tumours when exposed to omeprazole but at doses 4 to 352 times the human dose9. However mice also developed gastric carcinoids when exposed to high doses of histamine 2 receptor antagonists10.
Evidence: Two recent systematic reviews have been unable to demonstrate a single case of neither neoplasia nor evidence to suggest accelerated progression to pre-neoplastic lesions. H. pylori positive patients have a significantly increased risk of developing ECL hyperplasia and corpus atrophy compared to H. pylori negative patients11,12.
Conclusion: Although PPIs may cause ECL hyperplasia and corpus atrophy, particularly in the H. pylori infected patient, the clinical relevance is uncertain. It would be prudent to eradicate patients of H. pylori if considering long term PPI therapy.
HYPOMAGNESAEMIA
Mechanism: Incompletely understood. Suggestion that the increased pH caused by PPIs affects transient receptor potential melastatin channels (types 6 and 7) and results in reduced active transport and absorption of magnesium1.
Evidence: There have been 14 case control, cross-sectional studies. Of these 11 demonstrated an association: six found a tendency towards hypomagnesaemia with two a more pronounced association in patients concurrently treated with diuretics and carboplatin or cisplatin and two others finding an association in patients with poor renal function13. In the most recent systematic review the pooled relative risk was 1.43 (95% CI, 1.08-1.88) in patients on PPIs14.
Patients frequently present with other electrolyte abnormalities, particularly hypokalemia and hypocalcaemia. There appear to be differences in the risk of hypomagnesaemia development between different PPIs, with pantoprazole demonstrating the highest risk and esomeprazole the lowest15. Case reports have reported a return to normal magnesium levels following discontinuation of the PPI and recurrence even with a different PPI, suggesting a class effect. Long-term usage has the highest risk1.
Conclusion: Observational studies confirm an association but this association is higher when other risk factors are present. Although hypomagnesaemia is rare, it is important given the potential for life threatening complications. Particular attention should be paid to patients with additional risk factors including intestinal malabsorption or renal wasting, more so in patients on long term PPI therapy16.
IRON MALABSORPTION
Mechanism: The majority of dietary iron is in the ferric form (Fe3+). The acidic pH of the stomach allows dissociation of iron salt from ingested food and converts this into a ferrous state (Fe2+), which allows it to be absorbed by the duodenal enterocytes. This process is facilitated by vitamin C, which acts as a reducing agent and prevents the formation of insoluble compounds. PPIs may also reduce the bio-availability of vitamin C16.
Evidence: Much of the data on the subject is based on case series or case reports. Only one study (retrospective cohort) has explored this issue finding that chronic PPI use (> 1 year) resulted in a significant decline in all hematologic indices. This study is suboptimal given a small sample size, limited use of serum ferritin levels and the problem of residual confounding in observational studies17.
Another study showed suboptimal absorption of ferrous sulphate in patients taking omeprazole18. However, several other studies have failed to demonstrate an association19.
Conclusion: Although theoretically plausible, there is a paucity of evidence to make conclusive16.
VITAMIN B12 DEFICIENCY
Mechanism: Gastric acid facilitates the separation of vitamin B12 from dietary protein. This process is catalysed by pepsin, which only becomes activated at a pH less than 420.
Evidence: Studies examining the relationship between PPIs and vitamin B12 show conflicting results. A recent meta-analysis of observational studies found that long-term use of PPIs (> 2 years) is associated with an increased risk of vitamin B12 deficiency (HR 1.83, 95% CI 1.36–2.46)21. However, this analysis suffers from the inherent problems of observational studies together with problems associated with determinations of vitamin B12 deficiency.
This is important when considering that the sensitivity of vitamin B12 levels <200 pg/ml is 65-95% and specificity of 50% with overall false negative and positives around 50%. Increased methylmalonic acid and homocysteine levels increase the sensitivity to over 95%22. Furthermore, analysis of secondary outcomes in two randomised trials, LOTUS (Long-Term Usage of esomeprazole vs. Surgery for Treatment of Chronic GERD) and SOPRAN (Safety of Omeprazole in Peptic Reflux Esophagitis: A Nordic Open Study) found no significant differences in vitamin B12 levels among the treatment and control groups at five and 12 years respectively23. Conclusion: A causal relationship between PPI use and vitamin B12 deficiency cannot be established. Vitamin B12 deficiency is rare in individuals consuming a normal diet. Screening for deficiency may be appropriate only in patients at high risk including elderly patients, patients with malabsorptive states, pernicious anaemia and malnutrition20.
BONE DISEASE (FRACTURES/OSTEOPOROSIS)
Mechanism: Incompletely understood. It is postulated that PPIs induce a reduction in bone strength through impaired absorption of calcium and vitamin B12 together with the effects of induced hypergastrinaemia. An acid milieu is thought to aid calcium absorption. A reduction in vitamin B12 absorption causes a decrease in osteoblastic activity with a decrease in bone formation and a reduction in bone density and strength.
PPI associated hypergastrinaemia and possibly hypomagnesaemia stimulates parathyroid hormone production which leads to increased bone resorption and decreased bone strength24.
Evidence: All the data have come from observational studies and yielded conflicting results. A Canadian study which included 8 340 patients, did bone mineral density scanning at baseline and follow up scans at 5 and 10 years, found that PPI users had lower bone mineral density at baseline but at 10 years had no accelerated density loss when compared to non-users. A recent meta-analysis found PPI users at increased risk for fractures (RR 1.33; 95% CI 1.15-1.54).
However, there was significant heterogeneity between the studies and not all studies accounted for most confounding factors25. Furthermore, most of these studies were carried out in the Nordic and Anglo-Saxon countries where there is a higher prevalence of fragility fractures20. The previously mentioned LOTUS and SOPRAN studies also failed to demonstrate an association23.
Conclusion: Currently there is insufficient evidence to suggest PPIs cause osteoporosis or accelerated bone mineral density loss. Any association is likely related to a combination of PPI therapy and other independent risk factors for osteoporosis24. At this stage there is not enough evidence to support calcium supplementation or regular BMD scans.
RESPIRATORY INFECTION
Mechanism: Incompletely understood. It is hypothesised a high pH may result in bacterial colonisation of the upper GI tract, changes of the microflora and increased pulmonary micro-aspiration20.
Evidence: The most recent systematic review found an increase in community acquired pneumonia (RR 1.49; 95% CI 1.16-1.92) and risk of hospitalisation with pneumonia (OR 1.61; 95% CI 1.12-2.31). Interestingly, patients were at highest risk in the first month of treatment. Neither dose nor patient age was found to be a risk factor26. However this study included mostly observational data and four randomised trials and thus was subject to several sources of bias particularly confounding and protopathic bias.
A multicentre study that addresses the possible protopathic bias by looking at a cohort prescribed PPI for non gastro-oesophageal indications (patients on non steroidal anti-inflammatory drugs) found no increase in hospitalisation among PPI users27. Interestingly, a meta-analysis looking specifically at critically ill patients on PPIs for stress ulcer prophylaxis also found no increased risk of pneumonia and no effect on mortality or length of ICU stay28.
Conclusion: In the absence of high quality studies, it is difficult to attribute PPIs as a causal factor. The inconsistent association, relatively low risk and the lack of a definite mechanism suggest that the positive results may be due to confounding factors.
SPONTANEOUS BACTERIAL PERITONITIS
Mechanism: Incompletely understood. Hypothesised that PPIs facilitate proliferation of bacteria by increasing gastric pH. This results in bacterial colonisation, overgrowth and translocation. Experimental studies in rats have shown that PPIs induce bacterial overgrowth20.
Evidence: Only observational studies are available and these have yielded conflicting results. In the latest meta-analysis of these studies, PPI use conveyed an increased risk of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis and ascites (OR 2.17; 95% CI 1.46-3.23). PPI use was also associated with an overall increase risk of bacterial infection29.
However in all these studies the authors failed to account for one or more confounding risk factors for SBP including increased age, low fluid protein concentration, high MELD or Childs Pugh score and increased international normalised ratio.
Conclusion: PPI use may be associated with an increased risk of infection in patients with chronic liver disease. Well-designed studies will be needed to prove this association. In the interim it would be prudent to exercise caution when prescribing PPIs to patients with chronic liver disease in particular Child-Pugh grades B and C20.
CLOSTRIDIUM DIFFICILE
Mechanism: Theoretically, acid suppression may lead to increased colonisation of the GI tract. However, C.difficile spores are resistant to the acidic gastric pH30. Another mechanism suggested by Imhann is an alteration of the gut microbiome by PPIs resulting in an environment that may predispose to C.difficile infection31.
Evidence: Four meta-analyses have analysed the available data with all coming to a similar conclusion: an increased risk of C.difficile in patients taking PPIs (OR 1.48-2.31)32-35. However, in the most recent meta-analysis, Tleyjeh concluded that the quality of evidence was very low and thus did not support a cause-effect relationship. There was unexplained heterogeneity between studies and residual confounding factors. Most studies failed to provide data with regard to treatment duration, co-morbid conditions, and hospitalisation.
PPI use may also increase the risk of recurrent C.difficile as demonstrated in four of five observational studies36.
Conclusion: No definitive conclusions can be made between the association of PPIs and the development of C.difficile. However, one needs to be cognisant of a possible association given the increasing prevalence and morbidity particularly in the elderly and in patients on broad-spectrum antibiotics.
DRUG INTERACTION – CLOPIDOGREL
Mechanism: PPIs are metabolised to its active form by the cytochrome P450 system in the liver (CYP2C19 and CYP3A4). Other drugs may also be metabolised in a similar way and this may lead to competitive inhibition.
Evidence: Clopidogrel is metabolised by the cytochrome P-450 system (CYP2C19) to its active form. The competitive inhibition by PPIs is supported by in vitro studies, which suggested a decreased clopidogrel inhibitory effect on platelets in patients taking omeprazole37. Several observational and four randomised studies sought to test if this interaction was clinically relevant38. This has yielded conflicting data with the randomised studies consistently showing no difference in ischaemic outcomes.
A demonstrable reduction in gastro-intestinal bleeding complications was evident. However, the 30 observational studies found an increase in ischaemic outcomes (HR 1.35; CI 1.18–1.54) and all-cause mortality (HR 1.32; CI 1.00–1.73) in patients taking PPIs (38). It is interesting that similar observational findings were found in the interaction of clopidogrel with statins and calcium channel blockers, which have subsequently been dispelled by randomised studies39. An additional factor to consider is the possible genetic polymorphisms of CYP2C19*2 and three alleles which have been shown to contribute to reduced function with differing prevalence among different race groups40.
Conclusion: There is no clear evidence that PPIs increase the risk of cardiovascular events in patients on clopidogrel.
DEMENTIA
Mechanism: PPIs enhance the production of amyloid-β protein, which has been associated with the development of Alzheimers.
PPIs cause a rise in gastrin releasing peptide, which has been shown to modulate brain functions related to anxiety and stress41. As stated previously, vitamin B12 deficiency may also contribute to neurology.
Evidence: A recent German observational study found PPI use to be associated with an increased incidence of dementia (hazard ratio, 1.44 [95% CI, 1.36-1.52]; P < .001). Subgroup analysis found no difference between omeprazole, pantoprazole and esomeprazole, despite the adjustments made for confounders, several residual confounders remained42.
Conclusion: Given the available data it is impossible to establish a causal relationship between PPI use and cognitive decline. Further studies are needed.
CONCLUSIONS
PPIs are a safe class of drug with most adverse events being minor in nature. Many of the associated adverse events are related to long-term therapy, often where there was no clear indication for use.
Most studies were observational in nature. These studies are prone to several sources of bias, particularly residual confounding and heterogeneity. The findings with regard to PPI adverse events are almost universally inconsistent. Furthermore, when looking at relative risk or odds ratios, a value of less than 2-3 is regarded by epidemiologists to be of weak association. Most of the studies discussed in this paper have a RR or OR of less than two20.
Despite the lack of data, the potential for adverse events should not be dismissed. The most important principles to apply are an individualised approach and use for only the most robust of indications24. There are subsets of patients (elderly, malnourished, immunocompromised, etc) who are at increased risk for many of the adverse events related to PPIs.
REFERENCES
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