B D Westerveld

VU University Amsterdam, Amsterdam, North Holland, Netherlands

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Publications (22)55.58 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: In recent years clinical interest in the study of the proteolytic enzymes of the stomach has greatly increased. Human pepsinogens belong to the group of aspartic proteases and are categorized into two main groups: Pepsinogen A (PGA = PG I) and Pepsinogen C (PGC = PG II). Genetic models have been proposed to explain the inheritance of PGA, and a recent multigene model may be of value. PGA phenotypes in urine and gastric mucosa have been determined in healthy volunteers as well as in patients with different gastric disorders. An increased frequency of the ‘intense Pg5’ phenotype seems to be associated with gastric cancer and pre-malignant conditions, such as atrophic gastritis. Reliable radio-immunoassay and enzyme-linked immunosorbent assay techniques have facilitated the study of serum levels of PGA and PGC in different patient groups; in particular, duodenal ulcer patients (high PGA levels) and patients with atrophic gastritis and/or gastric cancer (low PGA levels). The ratio serum PGA/PGC may be introduced for clinical application, being the most convenient non-invasive marker for the detection of fundic atrophy. While the chromosome localization of pepsinogen has been established, further research is likely to concentrate on the structure and organization of the pepsinogen genes at the DNA-level, as well as on the development of new isozyme specific monoclonal antibodies.
    Journal of Gastroenterology and Hepatology 03/2008; 1(5):401 - 415. · 3.33 Impact Factor
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    ABSTRACT: Helicobacter pylori causes chronic gastritis in all infected individuals and thus may be a risk factor for the ultimate development of trophic gastritis and gastric cancer. The serum levels of pepsinogen A, pepsinogen C and gastrin can be used as markers for both non-atrophic and atrophic gastritis. We determined the serum levels of gastrin, pepsinogen A and pepsinogen C and the pepsinogen A/C ratio in 150 H. pylori-negative and 186 H. pylori-positive individuals. The H. pylori infected patients had significantly higher serum levels of pepsinogen A, pepsinogen C and gastrin and a significantly lower pepsinogen A/C ratio. In the non-infected patients, none of the respective serum values changed with increasing age. In contrast, in the infected patients, the pepsinogen A level and pepsinogen A/C ratio decreased significantly with increasing age. H. pylori infection increases serum levels of pepsinogen A, pepsinogen C and gastrin and decreases the pepsinogen A/C ratio. In infected subjects, levels of pepsinogen A and the pepsinogen A/C ratio decrease with ageing. These findings support the concept of H. pylori as a risk factor for the development of atrophic gastritis.
    European Journal of Gastroenterology & Hepatology 03/1996; 8(2):153-6. · 1.92 Impact Factor
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    ABSTRACT: The pepsinogen A (PGA) isozymogens in the gastric mucosa and Barrett epithelium of a female patient with Barrett esophagus were studied on different occasions during a 3-year period by electrophoretic analysis of in vivo steady-state pepsinogen in biopsies by activity staining in combination with variant specific monoclonal antibodies and of de novo synthesized pepsinogen by autoradiography. In Barrett epithelium only one (Pg3) or two (Pg3 and Pg5) primary PGA gene products were detected, whereas in gastric mucosal biopsies three (Pg3, Pg4 and Pg5) primary gene products were demonstrated on all occasions. These differences strongly suggest differential expression/activation of individual gene numbers in the PGA gene cluster in Barrett esophagus and are in line with the preneoplastic nature of this condition. The mechanism behind this deregulation is currently under investigation by cell biology and molecular genetic techniques.
    Clinical Genetics 09/1988; 34(2):90-7. · 3.94 Impact Factor
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    ABSTRACT: The relationship between electrophoretic pepsinogen A (PGA) patterns from urine and gastric mucosa was studied in healthy volunteers and in patients with various gastric disorders. Discrepancies between urinary and gastric PGA patterns were found in 63.3% of the individuals. In 9% of the subjects with these discrepancies, the phenotype class in urine was different from that in gastric mucosa. The differences were found in all diagnostic groups. The highest frequency of differences was found in patients with gastric ulcer. The differences were not related to the serum PGA level. More than 80% of the differences were caused by a lower relative intensity of pepsinogen A fraction 5 (Pg5) in urine than in gastric mucosa. The possible origin of differences in PGA isozymogen patterns was studied by organ culture of gastric biopsies. In vitro synthesis and secretion of pepsinogens were studied by electrophoresis and autoradiography. The synthesis rate of PGA in biopsies of 1–2 mm diameter was 40–100 ng/hr. Posttranslational modification of PGA isozymogens was demonstrated. Pg2 and part of Pg4 probably are secondary products of Pg3 and Pg5, respectively. In some individuals the secretion rate ofPg3 was low compared to the other isozymogens. The conversion of Pg3 into Pg2 and the differential secretion of the isozymogens may explain some of the discrepancies between gastric and urinary PGA patterns.
    Digestive Diseases and Sciences 01/1988; 33(2):135-143. · 2.26 Impact Factor
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    ABSTRACT: Precursors of the gastric proteases pepsinogen A (pepsinogen I) and pepsinogen C (pepsinogen II) and slow-moving protease were demonstrated in biopsy specimens from Barrett's epithelium in 21 of 22 patients with Barrett's esophagus; in 14 of them, in variable combinations at different sites. In 13 of 19 patients (68.4%) with detectable pepsinogen A, different isozymogen patterns were found between the Barrett's epithelium and the gastric corpus mucosa. Discrepancies consisted mainly of a stronger pepsinogen 5 band in the Barrett's epithelium, with a higher incidence in biopsy specimens with features of dysplasia than with no or indefinite dysplasia; the difference was, however, not statistically significant. Zymograms of 69 biopsy specimens from Barrett's epithelium were correlated with the histologic type: pepsinogen A and C were most frequently found in the fundic type, least often in the specialized intestinal type. In control gastric corpus biopsy specimens, pepsinogen A and C as well as slow-moving protease were always detectable. The observed variability of gastric protease patterns, in particular of pepsinogen A isozymograms, may be due to differences in expression within the pepsinogen A cluster, suggesting a deregulation of gene expression or partial deletion of the pepsinogen A gene cluster.
    Gastroenterology 11/1987; 93(4):774-8. · 12.82 Impact Factor
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    ABSTRACT: Gastric mucosal pepsinogen A phenotype, serum pepsinogen A level, serum pepsinogen C level, serum pepsinogen A/pepsinogen C ratio, and serum gastrin level were evaluated as potential markers for gastric cancer or its precursors in 19 healthy volunteers and 341 patients from the gastroscopy program. Gastric cancer, atrophic gastritis, and intestinal metaplasia of the stomach were associated with pepsinogen A phenotypes, characterized by an intense fraction 5, and with a low serum pepsinogen A level (less than 25 micrograms/l), a low serum pepsinogen A/pepsinogen C ratio (less than 1.5), and a high serum gastrin level (greater than 79 ng/l). The specificity of pepsinogen A phenotypes with an intense fraction 5 for gastric cancer or its precursors was 95.1% with a sensitivity of 20.4%. The sensitivity and specificity of the noninvasive tests were evaluated with the receiver operating characteristic. For clinical purposes, a serum pepsinogen A/pepsinogen C ratio less than 1.8 is the most suitable test, with a sensitivity of 74% and a specificity of 76% for gastric cancer or its precursors, with a reference population of patients with benign gastric disorders. However, the sensitivity and specificity of the single or combined tests are too low for population screening purposes.
    Cancer 04/1987; 59(5):952-8. · 5.20 Impact Factor
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    ABSTRACT: Gastric mucosal pepsinogen A phenotype, serum pepsinogen A level, serum pepsinogen C level, serum pepsinogen A/pepsinogen C ratio, and serum gastrin level were evaluated as potential markers for gastric cancer or its precursors in 19 healthy volunteers and 341 patients from the gastroscopy program. Gastric cancer, atrophic gastritis, and intestinal metaplasia of the stomach were associated with pepsinogen A phenotypes, characterized by an intense fraction 5, and with a low serum pepsinogen A level (<25 μg/l), a low serum pepsinogen A/pepsinogen C ration (<1.5), and a high serum gastrin level (> 79 ng/l). The specificity of pepsinogen A phenotypes with an intense fraction 5 for gastric cancer or its precursors was 95.1% with a sensitivity of 20.4%. The sensitivity and specificity of the noninvasive tests were evaluated with the receiver operating characteristic. For clinical purposes, a serum pepsinogen A/pepsinogen C ration less than 1.8 is the most suitable test, with a sensitivity of 74% and a specificity of 76% for gastric cancer or its precursors, with a reference population of patients with benign gastric disorders. However, the sensitivity and specificity of the single or combined tests are too low for population screening purposes. Cancer 59:952-958, 1987.
    Cancer 02/1987; 59(5):952 - 958. · 5.20 Impact Factor
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    ABSTRACT: Electrophoretic pepsinogen A patterns were determined in gastric fundic mucosa biopsies from 601 patients with various gastric disorders and 25 healthy volunteers. Pepsinogen A patterns with an intense fraction 5 appeared to be associated with gastric cancer and premalignant changes of the stomach (p less than 10(-9)). In 60 individuals pepsinogen A patterns were determined in normal mucosa from different parts of the stomach. No differences were found between these patterns. In 29 out of 59 gastric cancer patients pepsinogen A could be demonstrated in the macroscopically malignant tissue. In two cases a different pattern compared with uninvolved fundic mucosa was observed. During a follow up study, major changes in the pepsinogen A pattern were observed in 7 out of 56 patients. In 8.6% of the examined patients urinary pepsinogen A patterns differed considerably as compared with the pattern observed in the gastric fundus. The results suggest that the highly significant association between intense Pg5 (the product of the D gene) and gastric cancer or its precursors may be caused by genetic as well as non-genetic factors.
    Clinical Genetics 10/1986; 30(3):202-12. · 3.94 Impact Factor
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    ABSTRACT: Total human pepsinogen (PG) was isolated from gastric fundic mucosa and PGA (formerly called PGI) from urine, using standard ion-exchange and gel filtration techniques. Gastric PGA was separated from PGC (formerly called PGII) either by immunoaffinity or high resolution ion-exchange chromatography (fast protein liquid chromatography, Pharmacia, Uppsala, Sweden). The individual PGA isozymogens 2, 3, 4 and 5 could be isolated to homogeneity with the aid of the same ion-exchanger. Evidence was obtained for the existence of secondary modifications of the PGA fractions 3, 4 and 5, electrophoretically overlapping the primary (genetic) isozymogens.
    Scandinavian Journal of Clinical and Laboratory Investigation 12/1985; 45(7):649-55. · 1.29 Impact Factor
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    ABSTRACT: Regulation mechanisms of pepsinogen (EC 3.4.23.) synthesis and secretion were studied by following newly synthesized [14C]-labeled pepsinogen during culture of isolated rabbit gastric glands.Omeprazole, a substituted benzimidazole, while almost completely abolishing acid production at 10−4M, strongly stimulated secretion of preformed and newly synthesized pepsinogen. Although the pepsinogen synthesis at this concentration of omeprazole was reduced to about 55% of the control rate, a two-fold absolute increase of total secreted pepsinogen was found. This increase was not due to a non specific leakage through disruption of chief cell membranes, as no increase of lactate dehydrogenase in the culture medium could be demonstrated.The stimulated secretion was influenced neither by 10−3 M cimetidine, 10−3 M sodium thiocyanate nor 10−4 M atropine. No additivity was found between the carbachol (10−4 M) or dibutyryl cyclic AMP (10−3 M) and the omeprazole induced pepsinogen secretion.
    Biochemical Pharmacology 11/1985; · 4.58 Impact Factor
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    ABSTRACT: Previous studies in rats have shown that stomach carcinogens cause a decrease of total pepsinogen content and a decrease of the fastest pepsinogen isozymogen in gastric mucosa before the appearance of carcinoma. In man the presence of Pg 5, and in particular a strong Pg 5, appears to be associated with gastric cancer. Low serum PG I levels were found in patients with gastric cancer, atrophic gastritis, intestinal metaplasia and gastric polyp. In this chapter we review the literature and report our results of PG I isozymogen and serum PG I determinations in 500 patients with various gastric disorders. It is concluded that premalignant changes of the stomach are associated with the presence of a strong Pg 5 isozymogen and with a low serum PG I level.
    Progress in clinical and biological research 02/1985; 173:201-12.
  • Nederlands tijdschrift voor geneeskunde 02/1985; 129(3):117-9.
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    ABSTRACT: Serum PG I levels were measured by an enzyme linked immuno sorbent assay (ELISA) in 567 blood donors and 171 patients from a routine gastroscopy program to study the relationship between PG I phenotypes and serum levels. In normal subjects no association was found between PG I phenotypes and serum levels. A low serum PG I level in patients was associated with phenotypes characterized by intense PG I fraction 5. This probably reflects the high frequency of these phenotypes in patients with atrophic gastritis or gastric cancer. The mean (+/- SD) serum PG I level was 45.8 +/- 17.7 micrograms/1 in control subjects. Serum PG I levels were lower in females (41.4 +/- 17.5) than in males (47.3 +/- 17.7) and increased with advancing age up to 65 years.
    Progress in clinical and biological research 02/1985; 173:91-100.
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    ABSTRACT: De novo synthesis of pepsinogens was demonstrated in gastric glands isolated from rabbit and human gastric mucosa. The isolated glands were incubated in an amino acid free, Minimum Eagles Medium supplemented with a 14C labelled amino acid mixture. The glands were centrifuged at different time intervals and aliquots of gland homogenates and medium were run on polyacrylamide slab gels. Newly synthesized pepsinogens were demonstrated by autoradiography. Incorporation of 14C was detected after 30 minutes of culture and increased almost linearily with time over 4 h. By comparing the electrophoretic patterns after autoradiography, protein and pepsinogen activity staining, it was concluded that the glands synthesize mainly pepsinogens. Cimetidine, at a concentration of 10(-4)M strongly inhibited pepsinogen synthesis. Spontaneous secretion of pepsinogens into the medium was very low and relatively constant. Cyclic dibutyryl AMP markedly stimulated the secretion of pepsinogens into the medium. The results show, that isolated gastric glands are capable of synthesis and secretion of pepsinogens and that each function can be stimulated and inhibited selectively.
    Progress in clinical and biological research 02/1985; 173:147-57.
  • The Netherlands Journal of Medicine 02/1985; 28(10):463-9. · 2.38 Impact Factor
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    ABSTRACT: An immunoperoxidase method using antisera specific for PG I and PG II was developed to assess PG-containing cells in the human stomach. Fundus-chief cells contained abundant PG I and less PG II. Mucus neck cells stained more frequently with anti-PG I, while antral gland cells stained only with anti-PG II. In adenocarcinoma of the corpus, isolated glands faintly staining with anti-PG I or anti-PG II were observed. In dense tumorous tissue no anti-PG I activity could be observed, while PG II sometimes remained present in residual antral glands, even in areas of heavy tumor infiltration. Focal PG II activity was also clearly demonstrated in some antral tumor cells. The immunoperoxidase technique described is suitable for further detailed studies of normal and pathological conditions of the gastric mucosa.
    Progress in clinical and biological research 02/1985; 173:185-97.
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    ABSTRACT: Serum pepsinogen A (pepsinogen I) levels and urinary pepsinogen A phenotypes were studied in relation to ABO blood group, age and sex in 700 healthy blood donors. There was no relation between urinary pepsinogen A phenotypes and serum pepsinogen A levels. It is concluded that serum PGA levels and PGA phenotypes are independent factors in predisposition to gastroduodenal disorders. Serum pepsinogen A levels were higher in males than in females and rose with increasing age. The ABO blood groups were not related to pepsinogen A phenotypes. Blood group O individuals showed higher serum pepsinogen A levels compared with blood group A. Pepsinogen A phenotypes with intensity of fraction 5 were more frequent in males compared with females.
    Annals of Human Biology 01/1985; 12(5):403-11. · 1.48 Impact Factor
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    ABSTRACT: De novo synthesis of pepsinogen was shown in isolated rabbit and human gastric glands after incubation of the glands in a 14C labelled amino acid enriched minimum Eagles medium. At regular intervals, glands and medium were separated and analysed by polyacrylamide gel electrophoresis. Newly synthesised pepsinogen was shown by autoradiography. Incorporation of 14C labelled amino acids was detected after only 30 min of culture and increased almost linearly in time for 4 h. By comparing the incorporation of label into total protein and into pepsinogen, it was concluded that pepsinogen formed 70-90% of the newly synthesised protein. Cimetidine, at a concentration of 160 micrograms/ml, strongly inhibited the synthesis of pepsinogen. Spontaneous secretion of pepsinogen into the medium was very low and relatively constant. Dibutyryl cyclic AMP considerably stimulated the secretion of pepsinogen into the medium. Histamine and pentagastrin did not influence the release of pepsinogen. These results show that isolated gastric glands are capable of synthesis and secretion of pepsinogen and that both can be selectively stimulated and inhibited.
    Journal of Clinical Pathology 06/1984; 37(5):531-6. · 2.44 Impact Factor
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    ABSTRACT: A new genetic model is proposed to explain the inheritance of the urinary pepsinogen (PG1) polymorphism. Each main fraction, 3, 4 and 5, in the multibanded electrophoretic pattern, is determined by its own specific gene, B, C and D respectively. The intensity ratio of the fractions is principally determined by the number of gene copies. Accordingly, the PG1 phenotypes are determined by gene combinations, haplotypes, some of which may be identical to alleles in previous one locus models. Some critical families, not interpretable using previous genetic models, are presented to support the hypothesis. Preliminary population data from the Netherlands are described. The molecular background of this polymorphism and its relevance for gastric (pre)malignancy is discussed.
    Human Genetics 02/1984; 65(4):385-90. · 4.63 Impact Factor
  • Nederlands tijdschrift voor geneeskunde 06/1983; 127(19):812-7.

Publication Stats

122 Citations
871 Views
55.58 Total Impact Points

Institutions

  • 1987–1996
    • VU University Amsterdam
      • Department of Gastroenterology and Hepatology
      Amsterdam, North Holland, Netherlands
  • 1985
    • University of Amsterdam
      • Department of Gastroenterology and Hepatology
      Amsterdamo, North Holland, Netherlands
  • 1984
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands