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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Background

: Omeprazole maintenance therapy for gastro-oesophageal reflux disease (GERD) has been associated with an increased incidence of atrophic gastritis in H. pylori-infected patients and with a decreased absorption of protein-bound, but not of unbound cobalamin.

Aim

: To test the hypothesis that the combination of decreased cobalamin absorption and atrophic gastritis decreases serum cobalamin levels during omeprazole therapy.

Methods

: Forty-nine H. pylori-positive GERD patients were treated with omeprazole for a mean (± s.d.) period of 61 (25) months. At the start of omeprazole treatment (T0) and at the latest follow-up visit (T1), serum was obtained for measurement of cobalamin. Corpus biopsy specimens were obtained at entry and follow-up for histopathological scoring according to the updated Sydney classification.

Results

: At inclusion, none of the 49 patients had signs of atrophic gastritis. During follow-up, 15 patients (33%) developed atrophic gastritis, nine of whom had moderate to severe atrophy. These 15 patients did not differ from the other 34 patients with respect to age, serum cobalamin at T0 or the duration of follow-up. During follow-up, no change was observed in the median serum cobalamin level in the 34 patients without atrophy; (T0) 312 (136–716) vs. (T1) 341 (136–839) pmol/L (P=0.1). In the 15 patients who developed atrophy, a decrease in cobalamin was seen from 340 (171 to 787) at baseline to 285 (156–716) at latest follow-up (P < 0.01).

Conclusions

: The development of atrophic gastritis during omeprazole treatment in H. pylori-positive GERD patients is associated with a decrease of serum vitamin B12 levels.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Cobalamin (vitamin B12) is an essential nutrient and cofactor for several enzymatic reactions. Deficiency of cobalamin, either induced by nutritional lack or deficient uptake can result in megaloblastic anaemia and subacute combined degeneration of the spinal cord. Atrophy of the gastric mucosa causes a decrease in acid output and intrinsic factor production, both factors leading to diminished absorption of cobalamin. Ultimately, this may lead to megaloblastic anaemia.

Food cobalamin is mainly protein-bound. After peptic digestion in the stomach and linkage to intrinsic factor in the duodenum, the unbound form is absorbed in the ileum. A decrease in peptic activity will diminish the release of cobalamin from its protein bond and may hence lead to decreased ileal absorption. We previously demonstrated that the absorption of protein-bound, but not of unbound cobalamin was diminished during therapy with omeprazole 40 mg o.d.1 Although this did not affect the mean serum cobalamin levels in patients with gastro-oesophageal reflux disease (GERD) treated for a mean of 56 months, some individual patients did show an unexplained marked decrease in their serum cobalamin level during treatment.1 We also previously demonstrated that long-term acid suppressive therapy with omeprazole in Helicobacter pylori-positive GERD patients is associated with increased development of corpus atrophy.2 Our hypothesis was that the combination of decreased protein-bound cobalamin absorption and the development of gastric mucosal atrophy in H. pylori-positive subjects treated with omeprazole could lead to a decrease in serum cobalamin levels. We tested this hypothesis in a longitudinal study in patients treated with omeprazole for GERD.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

In a prospective cohort study, patients referred to our out-patient clinic with symptoms suggestive of GERD, in particular heartburn, regurgitation or dysphagia, underwent flexible endoscopy of the upper gastrointestinal tract, following standard procedures and using Olympus Q10/20, GIF 100 or IT 100 endoscopes. Patients were eligible to enter the study if endoscopic oesophagitis grade 1 or more was present.3 Exclusion criteria were use of proton pump inhibitors, H2-receptor antagonists in a dose exceeding the equivalent of 300 mg ranitidine daily, or prokinetic drugs during the month prior to study entry, as well as previous major upper gastrointestinal surgery, known or suspected Zollinger Ellison syndrome, or hypochlorhydria due to (autoimmune) atrophic gastritis. After obtaining informed consent, each patient was subject to a clinical examination including a questionnaire concerning past medical history, drug use and a physical examination. After endoscopy, omeprazole was started at a dose of 40 mg o.d. Endoscopy was repeated after 3 months and at annual follow-up. The dose of omeprazole was tapered upon symptoms and endoscopical findings. The results with respect to the development of atrophic gastritis in these patients have been described previously.2

Biopsies

At each endoscopy a total of eight biopsy specimens were obtained. For histopathological examination, two antrum and four corpus biopsies were fixated in buffered formalin. After both haematoxylin-eosin and modified Giemsa staining, they were graded according to the updated Sydney system for both active and chronic gastritis, atrophy and presence of H. pylori.4 All biopsy specimens were scored by one pathologist who was unaware of clinical details and time of sampling. Moderate corpus atrophic gastritis was defined as a loss of at least 50% of gastric glands with fibrotic replacement or intestinal metaplasia within a corpus biopsy specimen; severe atrophic gastritis was defined as a (sub)total loss of gastric corpus glands within a specimen. Atrophic gastritis was scored according to the most severe abnormality found. One antrum and one corpus biopsy specimen were used for culture of H. pylori. A patient was considered H. pylori-infected if culture and/or histopathology was positive.

Laboratory assessments

Sera obtained before the start of omeprazole therapy and at the latest follow-up were used for measurement of cobalamin levels, by means of a radioimmunoassay (SimulTRAC-SNB, ICN). Normal serum cobalamin levels with this assay ranged from 180 to 800 pmol/L. The baseline results (T0) were compared with those of the latest follow-up (T1). During follow-up, haemoglobin levels were assessed for the presence of megaloblastic anaemia. Neurological assessments were not performed.

Statistical analysis

For statistical analysis the Wilcoxon rank sum-test was used. A two sided P-value < 0.05 was considered significant. The study was approved by the scientific and ethical committee of the Free University Hospital.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

A total of 49 Caucasian H. pylori-infected patients (27M, 22 F, mean age ± s.d. 63 ± 12 years) were included for analysis in this study. Mean duration (± s.d.) of treatment was 61 (±25) months. The median dose of omeprazole was 40 mg, ranging between 20 and 120 mg daily. None of the included patients had histopathological signs of corpus mucosal atrophy at baseline. However, at the latest follow-up, 15 out of 49 (33%) patients had developed atrophy, nine of whom had developed moderate to severe atrophy. No differences were observed with respect to age and duration of treatment between patients who developed atrophy and those who did not (Table 1).

Table 1.  . Patients divided by atrophy development during follow-up. At inclusion none of the patients had signs of atrophic gastritis. During the study period 15 patients developed corpus atrophic gastritis. No differences were found with respect to age, dose of omeprazole or duration of treatment between those patients who developed atrophic gastritis and those who did not Thumbnail image of

In the total patient group, median serum cobalamin levels did not change (314 vs. 314 pmol/L, Table 2). The proportional change in serum cobalamin levels during omeprazole therapy for patients with and without atrophic gastritis at follow-up are depicted in Figure 1. Patients not developing atrophy showed no change in serum cobalamin level during omeprazole maintenance treatment. However, in patients with atrophic gastritis a decrease in serum cobalamin level was observed, which was most pronounced in those 9 patients who developed moderate to severe atrophy. The median change in cobalamin levels during follow-up in patients with and without atrophy were –61 vs. +33%, respectively (P < 0.01; Table 2 and Figure 1). None of the patients had serum cobalamin levels below the lower limit of normal, nor signs of megaloblastic anaemia during omeprazole maintenance therapy.

Table 2.  . Vitamin B12 levels (median (range); pmol/L) in relation to histological status of the corpus mucosa at follow-up. Serum vitamin B12 significantly decreased in 15 patients who developed atrophy (Δ Vitamin B12–61 vs. +33, P < 0.01); the effect was most pronounced in those developing moderate and severe atrophy Thumbnail image of
image

Figure 1. . Median change from baseline (%) for serum vitamin B12 levels (thick bar) during follow-up for patients with and without atrophic gastritis. The upper and lower level of the boxes indicate the lower and higher quartiles, the brackets indicate 2.5% and 97.5% values.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Acid suppressive therapy has been shown to decrease the absorption of food cobalamin.1, 5 This is thought to be due to insufficient liberation of cobalamin from its protein-bond as a result of reduced acid output. Nevertheless, prolonged use of omeprazole has not been associated with a clinically important decrease in serum cobalamin. Recent publications have shown no change or only a mild decrease in cobalamin levels during omeprazole maintenance therapy over 3–4 years.1, 6, 7 Nevertheless, individual patients did show a marked unexplained decrease in serum cobalamin concentration. In these studies the role of H. pylori and gastric atrophy were not investigated. Abnormal food-cobalamin absorption tests have been reported in H. pylori-colonized healthy subjects not treated with acid suppression.8 It was suggested that H. pylori-induced gastritis predisposed to food-cobalamin malabsorption. This hypothesis may in particular be true for patients with H. pylori-induced multifocal atrophic gastritis.

In the present study we demonstrate that, in H. pylori-infected patients on long-term omeprazole therapy, development of atrophic gastritis of the corpus mucosa correlates with a significant decrease in serum cobalamin. Vitamin B12 is body stored to a considerable extent and even after complete depletion of food ingested cobalamin, clinically relevant deficiencies will usually develop only after 5–10 years. Therefore, even after the development of complete atrophy it will take many years before vitamin B12 deficiency becomes manifest. Our follow-up was too short for such an observation. We did not observe megaloblastic anaemia, and did not assess neurological functions. Although none of the patients in our study cohort developed vitamin B12 levels below the lower limit of normal, patients with H. pylori infection in conjunction with gastric atrophy may be at risk of the development of clinical relevant cobalamin decrease after long-term therapy. Monitoring of serum cobalamin levels after several years of omeprazole therapy can be recommended in these patients. Among our nine patients who developed moderate to severe atrophic gastritis, the degree of decline of serum cobalamin levels did not significantly correlate with the duration of treatment; however, the small number of patients strongly limits definite conclusions. Finally, we scored atrophic gastritis according to the most severe abnormality found. As gland loss may have a patchy distribution, we could thus in theory have overestimated the presence of atrophic gastritis. However, if so, one would expect that the association between gland loss and declining vitamin B12 levels would only have been stronger than reported here. In addition, we obtained at each endoscopy, more than twice the number of corpus biopsy specimens required by the updated Sydney classification and studied each patient up to 10 times at regular intervals. By doing so, we observed a high intra-individual reproducability of gland loss within specimens obtained at the same endoscopy, as well as over time with long-term follow-up. We therefore believe that the decline in vitamin B12 levels observed in patients who were diagnosed with atrophic gastritis truely reflects a result of decreased absorption due to a loss of gastric glands containing specialized cells.

In conclusion, H. pylori-infected patients who develop gastric atrophy during long-term omeprazole therapy may be at risk of the development of decreased serum cobalamin levels and measurement of cobalamin after long-term use is therefore advisable.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

This study was supported by Astra Hässle, Sweden and Astra Pharmaceutica b.v., the Netherlands.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References
  • 1
    Schenk BE, Festen HPM, Kuipers EJ, Klinkenberg-Knol EC, Meuwissen SGM. Effect of short- and long-term treatment with omeprazole on the absorption and serum levels of cobalamin. Aliment Pharmacol Ther 1996; 10: 541 5.
  • 2
    Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996; 334: 1018 22.
  • 3
    Savary M & Miller G. The Oesophagus. Switzerland: Solothurn, 1977.
  • 4
    Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. Updated Sydney system. Am J Surg Pathol 1996; 20: 161 81.
  • 5
    Steinberg WM, King CE, Toskes PP. Malabsorption of protein-bound cobalamin but not of unbound cobalamin during cimetidine administration. Dig Dis Sci 1980; 25: 188 92.
  • 6
    Koop H & Bachem MG. Serum Iron, ferritin, and vitamin B12 during prolonged omeprazole therapy. J Clin Gastroenterol 1992; 14: 288 92.
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    Koop H. Review article: Metabolic consequences of long-term inhibition of acid secretion by omeprazole. Aliment Pharmacol Ther 1992; 6: 399 406.
  • 8
    Carmel R, Pérez-Pérez GI, Blaser MJ. Helicobacter pylori infection and food-cobalamin malabsorption. Dig Dis Sci 1994; 39: 309 14.