Long-term safety of proton pump inhibitors: risks of gastric neoplasia and infections

After Helicobacter pylori eradication was introduced and largely eliminated the need for maintenance therapy for peptic ulcer disease, gastroesophageal reflux disease (GERD) became the main indication for prolonged gastric acid inhibition. The drug effect on GERD depends on the degree of acid inhibition, thus the efficacious proton pump inhibitors are preferred. The proton pump inhibitors have few immediate side effects, the main concern being the profound hypoacidity and hypergastrinaemia they induce. In short-term, hypergastrinaemia causes rebound hyperacidity, possibly worsening GERD and reducing the efficacy of histamine H₂ blockers. In the long-term, hypergastrinaemia causes enterochromaffin-like cell hyperplasia and carcinoids. Since enterochromaffin-like cells may be important in gastric carcinogenesis, iatrogenic hypergastrinaemia may predispose to carcinoma. Gastric hypoacidity also increases gut bacterial infections, and the barrier function of acid against viral and prion infections requires further assessment.     

Long-term safety of proton pump inhibitors: risks of gastric neoplasia and infections

After Helicobacter pylori eradication was introduced and largely eliminated the need for maintenance therapy for peptic ulcer disease, gastroesophageal reflux disease (GERD) became the main indication for prolonged gastric acid inhibition. The drug effect on GERD depends on the degree of acid inhibition, thus the efficacious proton pump inhibitors are preferred. The proton pump inhibitors have few immediate side effects, the main concern being the profound hypoacidity and hypergastrinaemia they induce. In short-term, hypergastrinaemia causes rebound hyperacidity, possibly worsening GERD and reducing the efficacy of histamine H(2) blockers. In the long-term, hypergastrinaemia causes enterochromaffin-like cell hyperplasia and carcinoids. Since enterochromaffin-like cells may be important in gastric carcinogenesis, iatrogenic hypergastrinaemia may predispose to carcinoma. Gastric hypoacidity also increases gut bacterial infections, and the barrier function of acid against viral and prion infections requires further assessment.     

长期使用质子泵抑制剂所致高胃泌素血症及其对策

质子泵抑制剂的应用是酸相关疾病的标准治疗。但是，长期使用对胃食管反流征患者可能存在潜在危害，例如低酸反馈所致的高胃泌素血症，肠嗜银细胞的增殖，潜在的胃部肿瘤诱发作用，停药后的酸反跳，幽门螺杆菌感染者胃泌酸区胃炎发生率增加，高胃泌素血症所致的其它肿瘤等。人们正在研究这些潜在危害，评价长期使用质子泵抑制剂的风险-效益比，并提出对应策略。     

Safety of proton pump inhibitors--an overview.

Drug-induced achlorhydria in experimental animals results in excessive hypergastrinaemia, ECL-cell hyperplasia and ECL-cell carcinoidosis. However, these events have not been observed in long-term studies in patients receiving proton pump inhibitors. Serum gastrin levels increase only modestly during acute and long-term treatment. It is concluded that monitoring of serum gastrin levels and of fundic ECL cells is of no clinical relevance even during long-term therapy with proton pump inhibitors. The clinically available proton pump inhibitors such as pantoprazole, omeprazole and lansoprazole are well tolerated, with a low incidence of side-effects. Minor and serious side-effects classified as possibly related to proton pump therapy have been described in up to 2.5% of patients. This is the same order of magnitude as that found in patients treated with H2-receptor blockers and in placebo-treated controls. In most cases, therefore, the observed side-effects are unrelated to the intake of proton pump inhibitors. Minor adverse events include headache, diarrhoea, dizziness, pruritus and rash. Proton pump inhibitors are metabolized mainly in the liver via the cytochrome P450 system and interactions with drugs metabolized by the same system are possible. Evidence is becoming available which suggests that pantoprazole may have less potential to interact with the cytochrome P450 system than the other proton pump inhibitors. In the case of diazepam metabolism, pantoprazole had the least effect on prolongation of the diazepam effect. This may well be an advantage in the clinical use of the drug.     

Review article: Pathogenesis and management of gastric carcinoid tumours

BACKGROUND: Gastric carcinoid tumours are rare, but are increasing in incidence. AIM: To discuss tumour pathogenesis and outline current approaches to patient management. METHODS: Review of published articles following a Pubmed search. RESULTS: Although interest in gastric carcinoids has increased since it was recognized that they are associated with achlorhydria, to date there is no definite evidence that humans taking long-term acid suppressing medication are at increased risk. Type I tumours are associated with autoimmune atrophic gastritis and hypergastrinaemia, type II are associated with Zollinger-Ellison syndrome, multiple endocrine neoplasia-1 and hypergastrinaemia and sporadic type III carcinoids are gastrin-independent and carry the worst prognosis. Careful investigation of these patients is required, particularly to identify the tumour type, the source of hypergastrinaemia and the presence of metastases. Treatment can be directed at the source of hypergastrinaemia if type I or II tumours are still gastrin responsive and not growing autonomously. Type III tumours should be treated surgically. CONCLUSIONS: Advances in our understanding of the pathogenesis of gastric carcinoids have led to recent improvements in investigation and management. Challenges remain in identifying the genetic and environmental factors, in addition to hypergastrinaemia, that are responsible for tumour development in susceptible patients.     

The role of proton pump inhibitors in the treatment of Zollinger-Ellison syndrome

Zollinger-Ellison syndrome is characterised by refractory peptic ulcer disease, diarrhoea and gastric acid hypersecretion associated with a gastrin-secreting tumour. The incidence is unknown, but, in the US, the frequency is 0.1-3.0 million people. Zollinger-Ellison syndrome is associated with multiple endocrine neoplasia type 1 in 25-35% of the cases. The diagnosis of Zollinger-Ellison syndrome is suggested when plasma gastrin is > 1000 pg/ml and the basal acid output is > 15 mEq/h or when associated with a pH < 2. The treatment is focused on controlling gastric acid hypersecretion and localisation of the tumour and its metastases. Proton pump inhibitors are the most effective antisecretory drugs and can be administered at high dosages. This review focuses on the role of the proton pump inhibitors in the management of gastric acid hypersecretion in Zollinger-Ellison syndrome.     

Omeprazole: A Comprehensive Review

Omeprazole is a member of a new class of substituted benzimidazoles. These agents inhibit the proton pump in the gastric parietal cell, blocking the final step in the gastric acid secretory pathway. Omeprazole has been investigated for the treatment of gastric ulcer, duodenal ulcer, gastroesophageal reflux, and various hypersecretory states. The prolonged inhibition of gastric acid secretion allows for once-daily dosing in patients with peptic ulcer disease and gastroesophageal reflux, and once- or twice-daily dosing in patients with Zollinger-Ellison syndrome. Compared with currently available therapies, omeprazole is well tolerated and demonstrates a more rapid ulcer healing rate. It is superior to conventional therapies in the treatment of Zollinger-Ellison syndrome. Side effects are infrequent when the drug is used for the short-term management of ulcers.     

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.     

Helicobacter pylori effects on gastritis, gastrin and enterochromaffin-like cells in Zollinger-Ellison syndrome and non-Zollinger-Ellison syndrome acid hypersecretors treated long-term with lansoprazole

BACKGROUND: Helicobacter pylori is said to cause atrophy of the gastric corpus and enterochromaffin-like cell proliferation in gastro-oesophageal reflux disease (GERD) patients treated long-term with a proton pump inhibitor. AIMS: To determine the effect of H. pylori infection on gastritis, enterochromaffin-like cell density and hyperplasia, mucosal atrophy and serum gastrin in patients with gastric hypersecretion (basal acid output gt; 15 mmol/h) with either hypergastrinemia (Zollinger-Ellison syndrome) or normal gastrin (non-Zollinger-Ellison syndrome) before and during long-term treatment with lansoprazole. METHODS: Lansoprazole was individually titrated to reduce basal acid output to < 5 mmol/h (< 1 mmol/h in post-surgical Zollinger-Ellison syndrome). Gastric corpus biopsies were obtained every 6 months before treatment and up to 8 years later. RESULTS: H. pylori was present in corpus biopsies in approximately 50%, causing active gastritis which resolved rapidly in 15 subjects after elimination of H. pylori. Patchy mild/moderate corpus atrophy was present at entry in two and at the end in four out of 60 patients, one being H. pylori-positive. Intestinal metaplasia (< 10%) was seen in six isolated biopsies (1% of total). H. pylori did not affect serum gastrin, enterochromaffin-like cell density or hyperplasia. Enterochromaffin-like cell density was twice as high in Zollinger-Ellison syndrome as in non-Zollinger-Ellison syndrome patients (241 vs. 126 cells/mm2, P < 0.001). Enterochromaffin-like cells remained normal in the non-Zollinger-Ellison syndrome hypersecretors regardless of H. pylori status. CONCLUSION: Corpus enterochromaffin-like cell increases were related to serum gastrin elevation, but neither H. pylori nor long-term treatment with lansoprazole alone or together had any effect on enterochromaffin-like cell density or hyperplasia. Corpus acute gastritis resulted from H. pylori infection, but did not result in mucosal atrophy despite long-term proton pump inhibitor treatment and promptly resolved with loss of H. pylori.     

Optimal treatment of Zollinger-Ellison syndrome and related conditions in elderly patients

Zollinger-Ellison syndrome is characterised by refractory peptic ulcer disease, severe diarrhoea and gastric acid hypersecretion associated with an islet-cell tumour of the pancreas (gastrinoma). The true incidence and prevalence of this rare disease is unknown; in the US, the frequency is one per one million people and the age at presentation varies from 7 to 90 years. Zollinger-Ellison syndrome is sporadic in 62-80% of cases and in 20-38% of cases is associated with multiple endocrine neoplasia type 1 (MEN 1). The diagnosis of Zollinger-Ellison syndrome is certain when the plasma gastrin is >1000 pg/mL and the basal acid output is >15 mEq/h in patients with an intact stomach, >5 mEq/h in gastrectomised patients, or when this hypergastrinemia is associated with a pH <2. The treatment is based on control of gastric acid hypersecretion and of the malignant tumour and its possible metastases.Proton pump inhibitors are the most effective antisecretory drugs and can be administered in the elderly at high dosages without drug-related adverse effects. As an initial therapy, daily dosages of omeprazole 80-100 mg or pantoprazole 40-160 mg are employed. In long-term treatment the doses can be greatly reduced once effective control of the gastric output has been established. Intravenous proton pump inhibitors may be administered when patients cannot take oral therapy, particularly in acute conditions. All sporadic localised gastrinomas should be excised if possible. When liver metastases are also present, their debulking may improve symptoms and survival, and facilitate medical treatment. There is some controversy as to the surgical approach for gastrinomas associated with MEN 1.Somatostatin analogues can be useful in reducing gastric acid hypersecretion, serum gastrin and gastric enterochromaffin-like (ECL) cells and can thus contribute to treating the disease more effectively. Their antiproliferative effect can be used in treating liver metastases. Chemotherapy is not the therapy of choice in patients with gastrinomas and is indicated only in those with malignant progressive disease; interferon alpha, embolisation and chemoembolisation are not advisable for the elderly.The treatment of elderly Zollinger-Ellison syndrome patients, similarly to all elderly oncological patients, should be based on the use of comprehensive geriatric assessment. This will enable the clinician to define the functional status of the elderly person, to decide whether the patient can tolerate surgery and/or the stress of antineoplastic therapy, and finally, to determine whether this patient can tolerate an aggressive treatment for Zollinger-Ellison syndrome or whether the only possible choice is palliative relief of symptoms.     

Review article: current perspectives on hypergastrinaemia and enterochromaffin-like-cell hyperplasia

Rabeprazole, a new benzimidazole proton pump inhibitor (PPI), is among a class of agents known to be very potent inhibitors of gastric acid secretion. PPIs inhibit hydrogen-potassium adenosine triphosphatase activity on the luminal surface of the parietal cell, effectively blocking the final common pathway for gastric acid secretion. Raising gastric pH stimulates the production of gastrin by G cells in the antrum of the stomach, which can lead to enterochromaffin-like (ECL)-cell hyperplasia. In the past, these changes have been viewed with concern, particularly in the light of studies in rats indicating that hypergastrinaemia and ECL-cell hyperplasia induce gastric carcinoid tumour formation. All available clinical data indicate that long-term PPI use does not lead to carcinoid tumour formation in humans. In fact, both serum gastrin elevation and ECL-cell hyperplasia are now generally viewed as normal physiological responses to gastric acid suppression. Serum gastrin concentrations, in particular, correlate well with gastric acid suppression, which has led to the use of gastrin response by some investigators as a surrogate marker of antisecretory effectiveness. Long-term tolerability data indicate that PPIs have a favourable side-effect profile. Data obtained from patients receiving acute or long-term maintenance rabeprazole therapy support this conclusion. Furthermore, neither animal nor human data obtained with rabeprazole suggest a significant risk for neoplastic changes secondary to hypergastrinaemia.     

Pantoprazole: a new proton pump inhibitor in the management of upper gastrointestinal disease

Pantoprazole, the third proton pump inhibitor (PPI) to become available, has been extensively investigated. Pantoprazole inhibits acid more powerfully than histamine H(2) receptor antagonists (H(2)RAs) and omperazole 20 mg and raises median 24-h gastric pH from about 1.5 to 3-4 in healthy volunteers and in duodenal ulcer patients to above 5. Results from studies have confirmed that pantoprazole is superior to H(2)RAs in speed of healing and symptom relief in patients with peptic ulcer. In patients with duodenal ulcer pantoprazole was as effective as omperazole 20 mg and in patients with gastric ulcer pantoprazole was statistically superior to omeprazole 20 mg after 4 weeks. In triple combination therapy of peptic ulcer disease, the mean eradication rate of Helicobacter pylori in data pooled from 32 pantoprazole-based studies was 86% and compliance with treatment was about 90%. Results pooled from 5 large clinical trials of gastroesophageal reflux disease showed healing rates significantly superior to those achieved with H(2)RAs and similar to those of other PPIs at 4 and 8 weeks. Symptom relief was more rapid with pantoprazole and maintenance treatment kept the majority of patients in remission; relapse rates at 1 year were 25-28% on 20 mg daily and 6-22% on 40 mg daily. Maintenance treatment with pantoprazole 40 mg has been shown to keep most patients with aggressive or refractory ulcer and reflux disease in remission for up to 3 years. Pantoprazole was also effective in the management of patients with Zollinger-Ellison syndrome. In volunteers given aspirin, pantoprazole 40 mg proved significantly superior to ranitidine and placebo in preventing the development of mucosal damage and was significantly better than placebo in preventing gastric ulcer and duodenal ulcer in arthritic patients on nonsteroidal antiinflammatory drugs. Clinical trials, postmarketing surveillance and long-term studies have confirmed that pantoprazole is effective and safe for the short- and long-term management of peptic ulcer and reflux disease, with side effects similar in incidence and type to those of H(2)RAs.     

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.     

Long-term use of proton pump inhibitors in GORD – help or hindrance?

Many patients with gastro-oesophageal reflux disease (GORD) experience chronic relapses and require maintenance therapy for symptomatic relief. This article reviews possible mechanisms for chronic relapse in GORD, and discusses the risks and benefits of proton pump inhibitors as maintenance therapy for this disease. Recent medical literature was reviewed to gather information about proton pump inhibitor therapy and GORD. The reports indicated that the tendency to relapse in GORD is probably related to ongoing motor defects and to the acid rebound that follows successful healing therapy. Proton pump inhibitors are very effective in maintaining symptomatic and endoscopic remission in GORD. Limitations of proton pump inhibitor therapy have largely so far been clinically irrelevant. Most side-effects are inherent consequences of any form of acid suppression therapy, and include hypergastrinaemia and rebound hyperacidity upon discontinuation of therapy. We conclude that the therapeutic balance tips toward proton pump inhibitors for treatment of GORD because their limitations are largely surpassed by excellent clinical efficacy, tolerance, and lack of serious adverse effects.     

Does the widespread use of proton pump inhibitors mask,complicate and/or delay the diagnosis of Zollinger–Ellison syndrome?

BACKGROUND: Proton pump inhibitors are potent acid suppressants which, at normal doses, can result in hypergastrinaemia in patients with idiopathic oesophageal reflux disease and in the control of symptoms in most patients with gastrinomas. Therefore, their use could delay or mask the diagnosis of gastrinoma. AIM: To investigate whether the widespread use of proton pump inhibitors masks or complicates the diagnosis of gastrinoma. SUBJECTS AND METHODS: Data from two centres with different referral criteria for suspected gastrinomas were analysed (Gastroenterology Unit, Rome, Italy and National Institutes of Health, Bethesda, MD, USA). The number of referrals and the number of new patients with gastrinoma diagnosed in the years prior to the widespread use of proton pump inhibitors (1986-1992) were compared with the numbers since proton pump inhibitors became widely available (1993-1998). RESULTS: The decrease in referral rate (P=0.0009) and the decrease in the annual rate of gastrinoma diagnosis (P=0.0020) at both centres correlated with the increased use of proton pump inhibitors. At the Italian centre, there was a 62% decrease in annual referrals (P < 0.0001) in the post-proton pump inhibitor period, relative to the pre-proton pump inhibitor period, whereas there was an increase in the rate of referral of other gastrointestinal endocrine tumours. The number of new cases of gastrinoma diagnosed decreased by 40%. At the US centre, the referral rate decreased by 28% (P=0.024) in the post-proton pump inhibitor period. There was also a 43% decrease in the number of new cases diagnosed annually in the post-proton pump inhibitor period (P=0.0012). There was a 2.6-fold increase in the post-proton pump inhibitor period in the percentage of referrals with a false diagnosis of gastrinoma as the cause of hypergastrinaemia (P=0.0040). CONCLUSIONS: In both referral centres, less patients have been referred with a possible diagnosis of gastrinoma and fewer new patients with gastrinoma have been diagnosed since proton pump inhibitors became widely available. These data support the conclusion that, since proton pump inhibitors have been released, the diagnosis of gastrinoma has been masked and will probably be delayed, with the result that patients with gastrinoma will be diagnosed at more advanced stages in their disease course.     

Long-term use of proton pump inhibitors in GORD – help or hindrance?

Many patients with gastro-oesophageal reflux disease (GORD) experience chronic relapses and require maintenance therapy for symptomatic relief. This article reviews possible mechanisms for chronic relapse in GORD, and discusses the risks and benefits of proton pump inhibtors as maintenance therapy for this disease. Recent medical literature was reviewed to gather information about proton pump inhibitor therapy and GORD. The reports indicated that the tendency to relapse in GORD is probably related to ongoing motor defects and to the acid rebound that follows sucessful healing therapy. Proton pump inhibitors are very effective in maintaining symptomatic and endoscopic remission in GORD. Limitations of proton pump inhibitor therapy have largely so far been clinically irrelevant. Most side-effects are inherent consequences of any form of acid suppression therapy, and include hypergastrinaemia and rebound hyperacidity upon discontinuation of therapy. We conclude that the therapeutic balance tips toward proton pump inhibitors for treatment of GORD because their limitations are largely surpassed by excellent clinical efficacy, tolerance, and lack of serious adverse effects.     

Rabeprazole: an update of its use in acid-related disorders.

Rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion. In 8-week studies, among patients with gastro-oesophageal reflux disease (GORD), rabeprazole 20 mg/day or 10mg twice daily was as effective as omeprazole and superior to ranitidine in the healing of GORD. Symptom relief with rabeprazole was superior to that provided by placebo and ranitidine and similar to omeprazole. In long-term trials rabeprazole 10 mg/day was similar to omeprazole 20 mg/day in a 2-year study and superior to placebo in 1-year studies, in both the maintenance of healing and prevention of symptoms in patients with healed GORD. In nonerosive GORD, 4-week studies have shown rabeprazole to be more effective than placebo in relieving heartburn and various other gastrointestinal symptoms. Data among patients with Barrett's oesophagus suggest rabeprazole 20 mg/day may be more effective than placebo in maintaining healing of associated oesophagitis after 1 year of treatment. One-week triple Helicobacter pylori eradication therapy with rabeprazole plus clarithromycin and amoxicillin achieved eradication rates of > or =85%. Rabeprazole is as effective as omeprazole and lansoprazole when included as part of a triple-therapy regimen for the eradication of H. pylori. Eradication rates of >90% were achieved when rabeprazole 20 to 40 mg/day was included as part of a quadruple eradication regimen. As monotherapy for peptic ulcer healing and symptom relief, 4- to 8-week studies have shown rabeprazole 10 to 40 mg/day to be superior to placebo and ranitidine and have similar efficacy to omeprazole. Preliminary 1-year data among 16 patients with Zollinger-Ellison syndrome suggest rabeprazole 60 to 120 mg/day can resolve and prevent the recurrence of symptoms and endoscopic lesions associated with this condition. In clinical trials of up to 2 years' duration the tolerability of rabeprazole is similar to that of placebo, ranitidine and omeprazole. Common adverse events assigned to rabeprazole have been diarrhoea, headache, rhinitis, nausea, pharyngitis and abdominal pain. Histological changes and increases in serum gastrin levels were unremarkable and typical of proton pump inhibitors. No dosage adjustment is necessary in renal and mild to moderate hepatic impairment. CONCLUSION: Rabeprazole is a well tolerated proton pump inhibitor. It has proven efficacy in healing, symptom relief and prevention of relapse of peptic ulcers and GORD and can form part of effective H. pylori eradication regimens. It is an important alternative to H(2) antagonists and an additional treatment option to other proton pump inhibitors in the management of acid-related disorders.     

An update on the available treatments for non-erosive reflux disease

Non-erosive reflux disease is defined as the presence of troublesome reflux symptoms, such as heartburn and regurgitation, in the absence of endoscopically-visible damage of the oesophageal mucosa. In comparison with erosive oesophagitis, non-erosive reflux disease is the most common clinical manifestation of gastro-oesophageal reflux disease. Pathophysiologically, it is not a homogeneous disease as only approximately two-thirds of patients have truly acid-related symptoms. This explains the fact that patients with non-erosive reflux disease consistently show a poorer response to proton pump inhibitor treatment than patients with erosive oesophagitis. Nevertheless, profound acid inhibition by proton pump inhibitors is the recommended first-line treatment in patients suffering from this condition, both in the initial phase and for long-term care. Non-responders to proton pump inhibitor therapy should be subjected to a thorough examination and treated on an individual basis. Emerging data on the long-term course of reflux disease under routine clinical care have led to the adoption of new therapeutic strategies that would have been unthinkable only a few years ago.     

Problems associated with the clinical use of proton pump inhibitors

Proton pump inhibitors have proven to be important in the treatment of acid/peptic diseases. However, their therapeutic uses have extended over time, which may alter their risk:benefit ratio. Significant rebound acid hypersecretion has been demonstrated, which persists for at least two months. Its clinical significance remains unknown. Enhanced oxyntic gastritis may be responsible for the increased acid suppressive effects of proton pump inhibitors in H. pylori-infected patients. It remains unclear whether either H. pylori eradication or diminishing rates of infection in the developed world will therefore decrease the efficacy of proton pump inhibitors. Problems with carcinoids in rodents have not been found in man. However, the consequences of very long-term use of proton pump inhibitors remain unknown. Similarly, the development of atrophic gastritis in H. pylori-positive patients treated with proton pump inhibitors, with the long-term concern of gastric carcinoma development, remains controversial.