Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors

This review examines the evidence for the development of adverse effects due to prolonged gastric acid suppression with proton pump inhibitors. Potential areas of concern regarding long-term proton pump inhibitor use have included: carcinoid formation; development of gastric adenocarcinoma (especially in patients with Helicobacter pylori infection); bacterial overgrowth; enteric infections; and malabsorption of fat, minerals, and vitamins. Prolonged proton pump inhibitor use may lead to enterochromaffin-like cell hyperplasia, but has not been demonstrated to increase the risk of carcinoid formation. Long-term proton pump inhibitor treatment has not been documented to hasten the development or the progression of atrophic gastritis to intestinal metaplasia and gastric cancer, although long-term studies are required to allow definitive conclusions. At present, we do not recommend that patients be tested routinely for H. pylori infection when using proton pump inhibitors for prolonged periods. Gastric bacterial overgrowth does increase with acid suppression, but important clinical sequelae, such a higher rate of gastric adenocarcinoma, have not been seen. The risk of enteric infection may increase with acid suppression, although this does not seem to be a common clinical problem with prolonged proton pump inhibitor use. The absorption of fats and minerals does not appear to be significantly impaired with chronic acid suppression. However, vitamin B12 concentration may be decreased when gastric acid is markedly suppressed for prolonged periods (e.g. Zolllinger-Ellison syndrome), and vitamin B12 levels should probably be assessed in patients taking high-dose proton pump inhibitors for many years. Thus, current evidence suggests that prolonged gastric acid suppression with proton pump inhibitors rarely, if ever, produces adverse events. Nevertheless, continued follow-up of patients taking proton pump inhibitors for extended periods will provide greater experience regarding the potential gastrointestinal adverse effects of long-term acid suppression.     

Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors

Background  Proton pump inhibitors (PPIs) may cause cyanocobalamin (vitamin B12) malabsorption, but measuring serum B12 alone may underestimate the prevalence. However, B12 deficiency elevates methylmalonic acid and homocysteine, both additional markers of B12 deficiency.
Aim  To determine the true prevalence of B12 deficiency and whether acid suppression by PPI caused it.
Methods  Sixty-one acid hypersecretors (basal acid output >15 mmol/h), 46 with gastrinoma [Zollinger–Ellison (ZE) syndrome] and 15 without [acid hypersecretor without gastrinoma (pseudo-ZE)], were treated with lansoprazole to determine its long-term (up to 18 years) pharmacological and clinical efficacy and safety, particularly as regards malabsorption of B12.
Results  Of 61 patients, six (10%) had low serum B12. Additional tests uncovered B12 deficiency in 13 (31%) of 41 still-available patients, despite normal serum B12. B12 replacement reduced elevated homocysteine and methylmalonic acid, supporting the diagnosis. Also, measuring both basal and stimulated gastric secretion, we found that acid suppression was neither prolonged nor profound enough to explain the B12 deficiency.
Conclusions  In long-term recipients of PPIs, B12 deficiency was more frequent (29%) than detected by measuring only serum B12, and there was not enough acid suppression to explain this deficiency.     

Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas

Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo-/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.     

Nutritional and life style determinants of plasma homocysteine in schizophrenia patients.

Recently, homocysteine levels have been reported to be elevated in young male schizophrenic patients. Since smoking, obesity, low folate or low vitamin B12 and various medications can increase homocysteine levels, we studied these variables and other clinical variables in 258 schizophrenic patients. A multiple linear regression for plasma homocysteine was performed on variables that were significantly related to plasma homocysteine. Variables predicting homocysteine levels in schizophrenic patients include gender, plasma folate levels, plasma vitamin B12 levels, mean red blood cell corpuscular volume and diastolic blood pressure. Only 24% of the variance in male patients was explained by the model. The reason for elevated plasma homocysteine in some schizophrenic populations remains unclear.     

Persistence and adherence to proton pump inhibitors in daily clinical practice

BACKGROUND: Proton pump inhibitors are widely used, but little is known about the usage pattern in different indications. AIM: To analyse proton pump inhibitor usage patterns in the general population. METHODS: A cohort of 16 311 incident proton pump inhibitor users was identified in the Integrated Primary Care Information database, a Dutch general practice research database. Persistence and adherence were calculated by indication. Risk factors were identified by logistic regression analysis. RESULTS: One-year persistence was 31% in patients using proton pump inhibitors for gastro-oesophageal reflux. Persistence was higher in oesophagitis grade A/B (54%), grade C/D (73%) and Barrett's oesophagus (72%), compared to patients with only reflux symptoms (27%). Approximately 25% of patients with non-reflux dyspepsia or Helicobacter pylori-associated indications used proton pump inhibitors for more than 6 months. Half of all patients used proton pump inhibitors <80% of time indicating intermittent use, which was independent of indication. Exception were patients with Barrett's oesophagus, who were most adherent. CONCLUSIONS: A substantial proportion of patients with indications not requiring long-term treatment use proton pump inhibitors for an extended period. Half of the patients used proton pump inhibitors on-demand or intermittently. Such usage pattern is probably sufficient for most patients, but may be inadequate if proton pump inhibitors are used for serious diseases, such as severe oesophagitis or Barrett's oesophagus.     

Effect of CYP2C19 polymorphism on serum levels of vitamin B12 in patients on long-term omeprazole treatment

BACKGROUND: The S-mephenytoin hydroxylase is a polymorphic cytochrome P450 (CYP) enzyme, identified as CYP2C19, which catalyses the metabolism of omeprazole and some other drugs. AIM: To determine whether long-term treatment with omeprazole affects serum vitamin B12 levels, and if so to what extent it depends on CYP2C19 activity. METHODS: Serum vitamin B12 levels (pmol/L) were assessed in 179 patients. Genotyping for wild-type (wt) and mutated (mut) CYP2C19 alleles was performed by allele-specific PCR amplification. RESULTS: One-hundred and eleven of the patients received one dose of 20 mg omeprazole. No difference in B12 levels were found between heterozygous (wt/mut) (n = 23) and homozygous (wt/wt) (n = 85) patients (mean +/- s.d., 350 +/- 82 vs. 315 +/- 87 pmol/L, respectively). Three patients were mut/mut, with serum vitamin B12 levels of 303 +/- 50 pmol/L. In the 68 patients on long-term (>1 year) therapy with 20 mg omeprazole daily, serum vitamin B12 levels were lower in the heterozygous (wt/mut) (n = 19) compared to homozygous wt/wt (n = 49) (246 +/- 71 vs. 305 +/- 98 pmol/L, P = 0. 01, respectively). In one patient (mut/mut) who was studied both after a single dose and after long-term (15 months) treatment with omeprazole, serum vitamin B12 decreased from 360 to 178 pmol/L. In the wt/mut, but not in the wt/wt group, serum vitamin B12 levels were significantly lower in patients on long-term therapy compared with those receiving one dose (246 +/- 71 vs. 350 +/- 82 pmol/L, P < 0.0001, respectively). CONCLUSIONS: CYP2C19 polymorphism significantly affected serum vitamin B12 levels in patients on long-term therapy with omeprazole. In the future, genotyping of CYP2C19 may be useful for patients in need of long-term treatment with omeprazole or other proton pump inhibitors.     

Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole

Background : The dramatic inhibitory effect of proton pump inhibitors on acid secretion has raised concern about possible side-effects, such as small bowel bacterial overgrowth, which may result in further gut dysfunction. The aim of this study was to assess the effect of proton pump inhibitors on duodenal bacteriology, carbohydrate absorption and bowel habit.
Methods : Small bowel bacterial overgrowth and xylose absorption were measured by culture of aspirated duodenal fluid and a combined 1 g ¹⁴C- d -xylose absorption–metabolism test in 20 patients with peptic ulcer disease. Tests were repeated after 4 weeks of treatment with omeprazole 20 mg daily. Intestinal transit was assessed by recording interdefecatory intervals and stool form.
Results : All patients showed an increase in duodenal bacterial counts following treatment, geometric mean counts increasing from 330 to 95000 CFU/mL. The geometric mean of the difference was 290 CFU/mL (95% CI, 110–720 CFU/mL; P <0.0001). No changes were noted in the xylose absorption or metabolism tests. Mean interdefecatory intervals decreased by 32% from 31.7 to 21.6 h, the mean difference being 10.1 h (95% CI, 1.6–18.5 h; P =0.01). The mean stool form index increased from 2.95 to 4.70, mean difference 1.75 (95% CI, 1.10–2.40; P <0.0001), with four patients reporting diarrhoea.
Conclusion : The results indicate that conventional treatment for duodenal ulcers with a proton pump inhibitor significantly increases bacterial colonization of the duodenum and the speed of intestinal transit.     

The prevalence of risk factors for gastrointestinal complications and use of gastroprotection among persons hospitalized for cardiovascular disease

BACKGROUND: Aspirin is often used in patients with cardiovascular disease, but it can also cause gastrointestinal complications. Proton pump inhibitors reduce the risk of gastrointestinal complications in aspirin users with a history of gastrointestinal complications. AIM: To determine the prevalence of gastrointestinal risk factors in aspirin users and the prevalence of proton pump inhibitor utilization in high-risk patients. METHODS: We reviewed all patients admitted to hospital between April and October 2004 with a diagnosis of cardiovascular disease. We collected data on demographics, medication use, comorbid illnesses, previous gastrointestinal complications, and medication use on admission and discharge. RESULTS: A total of 324 patients were admitted with cardiovascular disease of whom 94% were discharged on aspirin. Seventy-eight per cent of patients admitted had at least one gastrointestinal risk factor in addition to having cardiovascular disease, and 15% had three or more additional gastrointestinal risk factors. Patients with additional gastrointestinal risk factors were more likely to be prescribed proton pump inhibitor therapy (27% vs. 10%, P < 0.001). Only 10% of proton pump inhibitor-naíve high-risk aspirin users were prescribed a proton pump inhibitor upon discharge. CONCLUSIONS: The majority of high-risk aspirin users are not receiving proton pump inhibitors for gastroprotection. Further work is required to encourage providers to consider the use of gastroprotective strategies in appropriate patients.     

Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence

BACKGROUND: There is little evidence that treatment of patients with Barrett's oesophagus with proton pump inhibitors over periods up to 6 years results in major regression of Barrett's oesophagus. AIM: To determine if longer periods of treatment with proton pump inhibitors lead to significant regression of Barrett's oesophagus, and to determine the incidence of oesophageal adenocarcinoma in the proton pump inhibitor-treated patients. METHODS: We analysed prospectively-collected data on Barrett's oesophagus patients treated with proton pump inhibitors for 1-13 years. RESULTS: 188 patients with Barrett's oesophagus and intestinal metaplasia, were treated for 1-13 years with a proton pump inhibitor (966 years of treatment; mean 5.1 years). No change in length was seen during treatment but 48% of patients developed squamous islands (25% after 1-3 years; 100% at 12-13 years). Squamous islands correlated with treatment duration and male sex but not with proton pump inhibitor dose or patient age. Six patients developed dysplasia and three males developed adenocarcinoma during treatment (cancer incidence 0.31%). CONCLUSIONS: Proton-pump inhibitor treatment over 1-13 years does not shorten the Barrett's oesophagus segment but squamous islands appear in many patients. The incidence of oesophageal adenocarcinoma was low in these proton pump inhibitor-treated patients compared with published series.     

Capecitabine treatment results in increased mean corpuscular volume of red blood cells in patients with advanced solid malignancies

Capecitabine is a novel fluoropyrimidine carbamate which is selectively activated after oral administration to 5-fluorouracil (5-FU) by a sequential triple enzyme pathway in liver and tumor cells. The cytotoxic activity of the metabolized 5-FU depends on thymidylate synthase (TS) inhibition, leading to defective DNA synthesis. Capecitabine has shown promising activity in all tumor types sensitive to 5-FU and is therefore investigated in many clinical trials. Since we observed an increase of mean corpuscular volume (MCV) of red blood cells under therapy with capecitabine, the current investigation aimed to quantitate this effect and to elucidate the underlying mechanisms. A total of 154 patients suffering from advanced cancer received capecitabine (2500 mg/m2/day for 14 days every 21 days) either as monotherapy, or in combination with other antineoplastic agents or biological response modifiers. During 3 consecutive cycles of therapy a complete blood cell count including the red cell indices MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration was performed before each application of capecitabine. In addition, vitamin B12, folic acid and homocysteine were determined to define their role in increasing MCV. Restaging was performed after 9 weeks. Within 9 weeks, a statistically significant increase of MCV (without other hematologic abnormalities or clinical symptoms) could be observed (p<0.0001). Vitamin B12, folic acid and homocysteine levels did not change significantly during the observation period. When comparing the different increases of MCV during 9 weeks (deltaMCV) with respect to tumor response, deltaMCV tended to higher values in patients with tumor remission or stable disease than in patients with tumor progression. We conclude that serum levels within the normal range rule out severe deficiencies of vitamin B12, folic acid or homocysteine as an account of macrocytemia. We therefore hypothesize that an increased MCV (without concomitant anemia) in patients receiving capecitabine might be due to the 5-FU-induced TS inhibition also in erythroid precursor cells. Whether this increase in MCV might serve as a surrogate marker for tumor response has to be evaluated in further investigations.     

Homocysteine, vitamin B12 and folic acid levels in psoriatic patients and correlation with disease severity

Hyperhomocysteinaemia represents an independent risk factor for atherosclerotic cardiovascular disease, stroke, peripheral arterial occlusive disease and venous thrombosis. Psoriasis is a chronic inflammatory skin disease associated with increased atherothrombosis and cardiovascular risk profile. The aim of this study is to investigate homocysteine, folic acid and vitamin B12 levels in a cohort of psoriatic patients and its relationship with the severity of the disease. A retrospective observational study in 98 patients with chronic plaque psoriasis and 98 healthy controls was performed. Total plasma homocysteine level, folic acid, vitamin B12 and PASI index were assessed in every patient. Patients with psoriasis had plasma homocysteine levels higher than controls (57% of cases and 25% of controls; p<0.0001). Folic acid and vitamin B12 plasma levels were lower in psoriatic patients than in controls (p = NS), lower levels of vitamin B12 were found in patients with hyperhomocysteinaemia compared to patients with a normal value of homocysteine (p = 0.0009). The severity of psoriasis assessed according to PASI (19.51+/-16.26) did not directly correlate either with higher levels of homocysteine or with vitamin B12 and folic acid plasma levels. In conclusion, a significantly higher prevalence of hyperhomocysteinaemia was found in psoriatic patients compared to healthy controls. A significant correlation between hyperhomocysteinaemia and lower vitamin B12 levels, but not folic acid, was evidenced. On the contrary, our data do not correlate the high level of homocysteine with higher PASI scores or psoriasis type, suggesting that homocysteine level can be considered an independent risk factor in psoriatic patients.     

Personal review: alarmism or legitimate concerns about long‐term suppression of gastric acid secretion?

This article responds to controversial issues about the long-term use of acid suppression raised in a recent article in this journal by Waldum & Brenna. Although rebound acid secretion occurs following proton pump inhibitor therapy, the clinical significance of this is unclear, but the proposal that this is a major driver of acid-related diseases is considered implausible. The polypoid deformity of the gastric corpus that can occur with long-term proton pump inhibitor therapy is not neoplastic, and therefore has no bearing on other issues raised about proton pump inhibitor therapy and gastric malignancy. Current data in humans suggest that the magnitude of serum gastrin elevation from proton pump inhibitor treatment of up to 10 years, and any theoretical risks from this, have been overstated by Waldum & Brenna. Pernicious anaemia is a model of very doubtful validity for the risks of proton pump inhibitor therapy on several grounds. The proposal that diffuse gastric carcinoma arises from acid suppression-induced stimulation of enterochromaffin-like cells is challenged vigorously, because this is based on an implausible and substantially criticized interpretation of histopathology. It is agreed that it is appropriate to be cautious about the safety of long-term acid suppression, because no data are available for lifelong treatment in humans. Such caution should be tempered by a critical assessment of the benefits of this treatment in relation to any possible risks. The substantial data that now exist from long-term treatment of humans with proton pump inhibitors has not thus far revealed any definite risks. The risk of death from anti-reflux surgery, although small, would seem to far exceed any possible risks associated with long-term proton pump inhibitor use. Available data suggest that denial of the benefits of effective acid suppressant therapy to patients with clear-cut troublesome acid related disorders is an overreaction to concerns about the biological effects of inhibiting acid secretion with proton pump inhibitors.     

The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine

The objective of the present study was to examine the relationship between serum folate, vitamin B12, and homocysteine levels and the timing of clinical improvement to fluoxetine in major depressive disorder (MDD) patients. A total of 110 outpatients with MDD who responded to an 8-wk trial of fluoxetine had serum folate, B12, and homocysteine measurements at baseline (prior to fluoxetine initiation). Onset of clinical improvement was defined as a 30% decrease in Hamilton Depression Scale scores that led to a 50% decrease by week 8. Patients with low folate levels (0.05). In conclusion, low serum folate levels were found to be associated with a delayed onset of clinical improvement during treatment with fluoxetine in MDD by, on average, 1.5 wk.     

Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole

Aims To study the pharmacokinetics of three proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole, as well as any potential influence on CYP1A2 activity (measured by means of rate of caffeine metabolism) of these compounds at single dose and repeated dose administration.
Methods Fourteen healthy males, classified as 12 extensive metabolizers (EMs) and two poor metabolizers (PMs) according to the urinary S/R mephenytoin ratio, completed this open, randomized, three-way cross-over study. In each of the three 7-day treatment periods either omeprazole (20  mg), lansoprazole (30  mg) or pantoprazole (40  mg) in therapeutically recommended doses was administered once daily, and the pharmacokinetics of the proton pump inhibitors as well as the rate of caffeine metabolism was measured on days 1 and 7.
Results In the EMs there was an increase in AUC from day 1 to day 7 for omeprazole. In the PMs the AUC of both omeprazole and lansoprazole was unchanged during repeated dosing, while for pantoprazole there was a tendency to a slight decrease. The AUC at steady state was for all three proton pump inhibitors 5 fold higher in PMs compared with EMs, indicating that the same proportion of the dose, irrespective of compound, is metabolized by CYP2C19. No induction of CYP1A2 was evident for any of the compounds in either EMs or PMs.
Conclusions The ∼5 fold difference in AUC between EMs and PMs indicates that approximately 80% of the dose for all three proton pump inhibitors is metabolized by the polymorphically expressed CYP2C19. None of the three proton pump inhibitors, administered in therapeutically recommended doses, is an inducer of CYP1A2—neither in PMs nor in EMs.     

Discontinuation of proton pump inhibitors in patients on long-term therapy: a double-blind, placebo-controlled trial

BACKGROUND: The proportion of proton pump inhibitor users on long-term therapy who can discontinue proton pump inhibitor (PPI) medication without developing symptoms is unknown. AIM: To determine the proportion of patients on long-term PPI therapy who are able to discontinue PPIs without developing symptoms. METHODS: Patients on long-term PPIs, without a history of peptic ulcer or esophagitis underwent upper endoscopy. Patients were randomized double-blindly to taper down or continue a constant dosage of omeprazole for three weeks. Thereafter, all patients discontinued PPIs. RESULTS: Of the 97 patients enrolled, had used PPIs for 48 months, 78% had GERD. A total of 27% did not use PPIs during the year after discontinuation, 31% of the patients randomized to tapering discontinued PPIs and 22% of those who did not could discontinue therapy (NS). Gastro-oesophageal reflux disease (GERD) patients were more prone to continue PPIs than non-GERD patients. Only 16 (21%) of GERD patients were off PPIs vs. 48% of patients without GERD (p < 0.05). Serum gastrin was higher at baseline in GERD patients who resumed PPIs versus non-resumers (p < 0.05). GERD and serum gastrin were independent predictors of PPI requirement. CONCLUSIONS: Discontinuation of PPI was successful in 27% of long-term PPI users. GERD patients had more difficulty discontinuing PPIs than non-GERD patients.