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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

Background:

The polymorphic enzyme CYP2C19 is of importance for the metabolism and effects of omeprazole during short-term treatment.

Aim:

To investigate the relationship between CYP2C19 genotype and the effects of long-term omeprazole treatment.

Material and methods:

A total of 180 patients with acid related disorders were genotyped for wild type and mutated CYP2C19 alleles by allele-specific PCR amplification. Gastrin and chromogranin A were assessed by radioimmunoassays, and pepsinogen I and H. pylori serology were assessed by ELISA methods.

Results:

In 108 of the patients, who received a single dose of 20 mg omeprazole, there was no difference in gastrin and chromogranin A concentrations between the three CYP2C19 genotypes. In 72 patients on long-term treatment (> 1 year) with 20 mg omeprazole daily, serum gastrin as well as plasma chromogranin A concentrations (mean ± s.e.) were both about threefold higher in the wild type/mutated (52.1 ± 7.6 p M and 7.3 ± 1.3 n M (n=19), respectively) compared to wild type/wild type (14.7 ± 0.9 p M and 2.5 ± 0.1 n M (n=52), respectively; both comparisons P=0.0001). In a single mutated/mutated patient on long-term treatment, both gastrin and chromogranin A were high (88 p M and 13.7 n M, respectively). Serum pepsinogen I concentration was significantly lower in wild type/mutated (n=19) patients on long-term treatment, compared with the corresponding wild type/wild type (n=49) group (147 ± 19 μg/L vs. 193 ± 12 μg/L, P=0.04).

Conclusion:

Patients with one (and probably also with two) mutated CYP2C19 allele(s) on long-term treatment with omeprazole had significantly affected serum gastrin and pepsinogen I and plasma chromogranin A concentrations compared with patients with two normal alleles. This indicates that changes in gastric mucosal morphology during omeprazole treatment might be dependent upon the degree of the individual’s capacity to metabolize omeprazole.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

Omeprazole is a potent inhibitor of gastric acid secretion, widely used in the treatment of gastro-oesophageal reflux disease (GERD) and peptic ulcer disease.1, 2 Long-term continuous treatment of GERD is being increasingly used.3 Omeprazole is hydroxylated in the liver by cytochrome P450 2C19 (CYP2C19);4[5][6]–7 this enzyme is absent in about 3% of Caucasians and in as many as 12–20% of Orientals.8, 9 Such poor metabolizers have two mutated CYP2C19 alleles (CYP2C19*2 and/or *3). A higher frequency of heterozygous extensive metabolizers among Orientals (47%) compared with Caucasians (30%) has also been reported.10 The principal genetic defect found in poor metabolizers is a single G to A mutation in exon 5 of CYP2C19 (CYP2C19*2, previously called m1), and this accounts for about 93% of the defective alleles in Caucasians.11, 12 Another defect allele (CYP2C19*3, previously called m2) contains a G to A mutation in exon 4 and this is mainly found in Orientals.13 There are also studies indicating yet unknown mutations, causing the poor metabolizers phenotype.13, 14

The most abundant endocrine cells in the stomach are antral gastrin (G) cells and enterochromaffin-like cells of the fundic mucosa.15 Gastrin influences the growth of enterochromaffin-like cells, and, accordingly, hypergastrinemia is associated with hyperplasia of enterochromaffin-like cells in the fundic mucosa.16[17][18][19][20][21]–22 Chromogranins are large acidic proteins which are widely distributed in endocrine cells and neurones. The chromogranin family consists of at least three different members: Chromogranin A (CgA), chromogranin B (CgB), and chromogranin C. Recently, serum concentrations of CgA have been described as a reliable marker of neuroendocrine cell proliferation.23, 24 Increased serum CgA concentrations have been reported in patients with gastrinoma and patients with type A autoimmune gastritis.25, 26 Additionally, Waldum et al. reported elevated serum CgA levels after short-term treatment with omeprazole, suggesting its possible use as a test to evaluate enterochromaffin-like cell hyperplasia in patients with hypergastrinaemia secondary to acid inhibition.27 It has also been shown that after short-term acid inhibition by different drug regimens in healthy volunteers, serum gastrin and CgA increase in relation to the degree of acid inhibition.28

Human pepsinogen consists of two biochemically and immunologically different isozymes: pepsinogen I and pepsinogen II. Pepsinogen I is secreted by chief cells in the gastric corpus mucosa. Atrophic gastritis of corpus mucosa can be detected with high certainty by low serum pepsinogen I levels.29

The administration of omeprazole to humans increases the gastrin concentrations in the blood, and in some cases causes hypergastrinemia.30 Such hypergastrinemia is believed to be caused by decreased intragastric acidity leading to increased antral gastrin cell activity. Our hypothesis is that the effect of acid inhibition by omeprazole on gastrin and fundic mucosa are affected by the CYP2C19 polymorphism. Therefore, we studied the long-term effects of omeprazole on serum gastrin and pepsinogen I and plasma CgA in relation to CYP2C19 polymorphism.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

Patients

A total of 180 patients with acid related disorders (peptic ulcer disease and gastro-oesophageal reflux with oesophagitis) were included in this study. Of these, 108 were studied after their first dose of 20 mg omeprazole taken orally. These patients were from a previous study where we found an agreement between the CYP2C19 phenotype and genotype.14 None of these patients had taken any acid-suppressive drugs prior to inclusion. The remaining 72 patients had been treated continuously for more than 1 year (median 32 months; range 12–84 months) with a daily dose of 20 mg omeprazole, before inclusion. Data on vitamin B12 levels in these patients has been presented in a previous study.31 None of the 180 patients were taking any other drugs known to be metabolized by the CYP2C19 isozyme. All patients gave their informed consent and the study was approved by the ethics committee at Huddinge University Hospital.

Genotyping

Leucocyte nuclei were prepared from 10 mL of peripheral venous blood. DNA was prepared using standard methods. The CYP2C19*2 allele was identified by polymerase chain reaction-based amplification.11 The amplified polymerase chain reaction products were digested overnight with the restriction enzyme Sma I. Both digested and undigested polymerase chain reaction products were analysed by agarose gel electrophoresis. Similarly, the CYP2C19*3 allele was analysed by polymerase chain reaction amplification of exon 4 of CYP2C19, followed by digestion with the restriction enzyme Bam HI.13

Analysis of serum gastrin

All patients took an oral 20 mg dose of omeprazole as encapsulated enteric-coated granules (Losec, Astra-Hässle, Sweden) after an overnight fast. A 10-mL venous blood sample was drawn 3 h after drug intake; patients fasted until sampling. Serum was separated and stored frozen at –20 °C until analysis. Serum gastrin was determined by a competitive radioimmunoassay in accordance with Lundqvist and Wide, with minor modifications, using antiserum 90184, generously supplied by Professor Jens Rehfeld (Rigshospitalet, Copenhagen, Denmark).32 The normal gastrin concentration is < 50 p M.

Analysis of plasma chromogranin A

Plasma CgA was measured by a radioimmunoassay as previously described.23, 24 The normal plasma chrmogranin A concentrations is < 4.0 nmol/L.

Analysis of serum pepsinogen I

Serum pepsinogen I concentrations were analysed by a commercial enzyme linked immunosorbent assay (ELISA; Gastroset pepsinogen I, Orion Diagnostica, Espoo, Finland). The reference range is 28–158 μg/L.

H. pylori serology

H. pylori status was determined by serology with a previously validated method.33, 34 An in-house ELISA technique was used to measure specific IgG and IgA H. pylori antibodies.

Statistics

Data were expressed as mean ± s.e. The Mann–Whitney U-test was used to analyse differences between the groups. P-values of < 0.05 were considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

A total of 180 patients with acid related disorders were included in this study. Of 108 patients studied after their first dose of 20 mg omeprazole, 83 were homozygous for the wild type allele (wild type/wild type, i.e. CYP2C19*1/*1), 23 were heterozygous for the mutatedated alleles (wild type/mutated, i.e. CYP2C19*1/*2 or CYP2C19*1/*3) and two were homozygous for the mutated alleles (mutated/mutated, i.e. CYP2C19*2/*2). Among 72 patients on long-term maintenance treatment with a daily dose of 20 mg omeprazole, 52 were wild type/wild type, 19 were wild type/mutated and one patient was mutated/mutated. Patients were grouped according to their genotype and length of treatment. Demographic data and clinical diagnosis are listed in Table 1.

Table 1.  Demographic data for the CYP2C19 genotypic groups Thumbnail image of

Serum gastrin

There was no significant difference in the mean concentration of serum gastrin after the first dose between wild type/wild type and wild type/mutated groups of patients (Table 2). In patients on long-term treatment, the mean concentration of serum gastrin was higher in the wild type/mutated group compared with the wild type/wild type group (Table 2). Further, in the wild type/mutated group, but not in the wild type/wild type group, serum gastrin concentration was significantly higher (P < 0.0001) in patients on long-term treatment compared with corresponding groups of patients receiving one dose (Table 2).

Table 2.  Serum gastrin (p M), plasma chromogranin A (n M), and pepsinogen I (μg/L) concentrations after first dose and after long-term treatment with 20 mg omeprazole in the wild type/wild type and wild type/mutated groups of patients and when subgrouped according to their H. pylori status Thumbnail image of

Plasma chromogranin A

As for gastrin, no significant difference in the plasma CgA concentrations could be seen after the first dose between wild type/wild type and wild type/mutated groups of patients (Table 2). However, in patients on long-term treatment, the mean concentration of plasma CgA was higher in the wild type/mutated group compared with the wild type/wild type group (P=0.0001, Figure 2). Mean CgA concentration was also higher in the wild type/mutated group of patients on long-term treatment compared with the wild type/mutated group, who received just one dose (P=0.0001, Table 2). The patients in the mutated/mutated group were too few to allow statistical comparison.

Overall, there was a positive correlation between chromogranin A and gastrin concentrations (n=72, r=0.80, P < 0.0001; Figure 1).

image

Figure ure 1. Plasma chromogranin A concentrations vs. serum gastrin concentrations in the three genotypic groups of patients with reflux oesophagitis on long-term treatment with 20 mg omeprazole daily (○ wild type/wild type, n=52; □ wild type/mutated, n=19; ▵ mutated/mutated, n=1). The Spearman rank correlation coefficient is 0.80 (P < 0.0001).

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Serum pepsinogen I

No plasma was left for analysis of pepsinogen I in patients who received one dose of omeprazole. Additionally, a shortage of plasma left for analysis occurred in three out of 52 wild type/wild type patients on long-term treatment and in the one mutated/mutated patient.

The mean serum pepsinogen I concentration in patients on long-term treatment was lower in the wild type/mutated (n=19) group compared with wild type/wild type (n=49) group (P=0.04, Table 2).

H. pylori serology

In patients taking the first dose of 20 mg omeprazole, 62 patients were H. pylori-positive (49 wild type/wild type and 13 wild type/mutated) and, 44 patients were H. pylori-negative (34 wild type/wild type and 10 wild type/mutated). There were no significant differences in the serum gastrin and plasma chromogranin A concentration between H. pylori-positive and negative groups of patients within the wild type/wild type and wild type/mutated groups of patients and between the wild type/wild type and wild type/mutated groups of patients (Table 2).

In patients on long-term treatment, only 14 patients were H. pylori-positive (13 wild type/wild type and one wild type/mutated). Within the H. pylori serology-negative group, the significant differences between the genotypic groups were maintained.

Within the wild type/wild type group of patients on long-term treatment, there was no difference in plasma chromogranin A between H. pylori-positive and negative patients. However, serum gastrin was significantly (19 ± 1.7 p M vs. 13 ± 0.9 p M; P < 0.01) higher in the H. pylori-positive group compared to the wild type/wild type H. pylori-negative group on long-term treatment. A somewhat lower pepsinogen I levels was seen in the H. pylori-positive compared to the negative group (169 ± 22 μg/L vs. 202 ± 14 μg/L; N.S.) but the difference did not reach the significance (Table 2).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

To our knowledge, there are no published studies that explore the relationships between CYP2C19 genotype and the effect of long-term treatment with omeprazole or other proton pump inhibitors on gastrin, pepsinogen I, and chromogranin A concentrations in blood. As omeprazole metabolism is determined by the genetic polymorphism of CYP2C19, patients with defective CYP2C19 alleles have a decreased ability to metabolize the drug and are thus building up higher blood concentrations of omeprazole.6, 7, 12, 14 This will result in a more pronounced acid inhibition, which in turn could be the reason for higher gastrin and chromogranin A levels.

The data presented in this study show that serum gastrin and plasma chromogranin A concentrations were significantly higher in the heterozygote (wild type/mutated) patients on long-term omeprazole treatment compared to those receiving the first dose. The increase in gastrin concentrations is consistent with our finding in a previous study, where we found that treatment with 20 mg omeprazole daily for 8 days resulted in a greater magnitude of gastrin release in both wild type/mutated and mutated/mutated groups of healthy subjects, compared to the wild type/wild type group.35 Similar results were shown recently in patients with acid related disorders, by us, and in a Japanese study.36, 37 Hence, the effects of omeprazole on intragastric acidity and gastrin secretion are significantly affected by CYP2C19 polymorphism.

The clinical relevance of drug-induced hypergastrinemia has previously been addressed. The magnitude of hypergastrinemia is believed to be related to the degree and duration of gastric acid inhibition. Long-term treatment with omeprazole 40 mg daily in humans resulted in moderate hypergastrinemia (> 4 times of the normal) in 77% of the patients and in more severe hypergastrinemia in 23% of the patients.3

The main interest has so far been focused on the trophic effect of gastrin on the enterochromaffine-like cells located in the oxyntic mucosa of the stomach during states of hypergastrinemia. Long-term treatment with high doses of omeprazole in rats induced enterochromaffin-like cell hyperplasia, and even carcinoid (enterochromaffin-like omas) formation.38 In man, long-term treatment with omeprazole and other acid suppressive drugs has been shown to result in hypergastrinemia and a significant endocrine (argyrophil) cell hyperplasia in the corpus mucosa of the stomach.3, 39[40][41][42]–43

Additionally, recently the importance of H. pylori infection for development of morphological changes in the oxyntic mucosa in patients on long-term omeprazole treatment has been brought forward and debated. Kuipers et al. have shown that oxyntic mucosal gastritis worsen in H. pylori infected patients during treatment with omeprazole.44 Treatment with lansoprazole (another proton pump inhibitor metabolized by CYP2C19) 30–90 mg daily for up to 5 years has been shown to increase both atrophy of the oxyntic mucosa and argyrophil cell hyperplasia in 30% of H. pylori-positive patients.41 It is well documented that H. pylori causes chronic active gastritis in the oxyntic part of the stomach, which can progress to chronic atrophic gastritis after several years.45 Long-term treatment with proton pump inhibitors seems to worsen fundic gastritis and to accelerate the progression of atrophy in H. pylori infected patients.41[42]–43 Furthermore, even short-term treatment with omeprazole 40 mg daily seems to increase corpus gastritis in patients.46 Thus, not only H. pylori infection but also the degree of acid inhibition might be of importance for the development of gastric atrophy.

We have used chromogranin A as an indicator for enterochromaffin-like cell hyperplasia. Serum pepsinogen I has been used as an indicator for atrophic gastritis of the corpus mucosa. Our results show that the wild type/mutated group of patients on long-term treatment with omeprazole have significantly higher levels of circulating chromogranin A compared to wild type/wild type patients. As an increased concentration of chromogranin A has been shown to correspond to an increased number of enterochromaffin-like cells in omeprazole treated patients, our results indicate that it is the patients with a decreased ability to metabolize proton pump inhibitors who are mainly at risk to develop enterochromaffin-like cell hyperplasia.

Serum pepsinogen I levels are reported to rise after administration of omeprazole or other proton pump inhibitors, both after short and long-term treatment.47[48][49]–50 This study showed somewhat lower serum pepsinogen I in the wild type/mutated group of patients compared to wild type/wild type group. The explanation for low serum pepsinogen I in these patients might be a development of atrophic gastritis in some of the patients on treatment. Since all except one of the patients in this group were H. pylori-negative, we suggest that the degree of acid inhibition might be of some importance for the development of gastric atrophy in patients with mutated allele and on long-term treatment with omeprazole or other proton pump inhibitors. Our results show that the individual capacity to metabolize omeprazole, as well as H. pylori status, influence the magnitude of gastrin response during long-term treatment with omeprazole, and most likely during treatment with other proton pump inhibitors.

Blood sampling for the determination of the CYP2C19 genotype before long-term treatment with proton pump inhibitors could ideally lead to an adjustment of the dose in the individual patient in order to maintain a sufficient acid inhibition and a good clinical response, and at the same time minimize the risk for development of enterochromaffin-like cell hyperplasia and atrophic gastritis. Testing for CYP2C19 genotype or phenotype seems even more relevant in Orientals where the frequency of mutated CYP2C19 alleles is higher than in Caucasians. However, before considering testing in larger clinical settings, prospective studies in patients on long-term treatment with proton pump inhibitors and the correlation between CYP2C19 polymorphism and the morphological effects on the oxyntic mucosa in H. pylori-positive and negative patients are needed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

This study was supported by grants from the Swedish Medical Research Council (3902), the EU Biomed 2 (BMH4-CT 96–0291), the Swedish Society of Medicine, and the Karolinska Institute.

Bibliography

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography
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