Q J Med 1999; 92: 373-377
© 1999 Association of Physicians
The rise in circulating gastrin with age is due to increases in gastric autoimmunity and Helicobacter pylori infection
From the Altnagelvin Hospital, Londonderry, Northern Ireland, The Regional Regulatory Peptide Laboratory, Royal Victoria Hospital, Belfast, and 1 Departments of Medicine and 2 Bacteriology, The Queen's University of Belfast, Belfast, UK
Received 28 January 1999 and in revised form 7 May 1999
Dr J.E.S. Ardill, Regional Regulatory Peptide Laboratory, Mulhouse Building, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BJ
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Summary |
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To assess the effect of increasing age on circulating gastrin, we surveyed serum gastrin, Helicobactor pylori seroantibody status and gastric autoimmunity in 366 hospitalized patients aged 15–90 years. Data were subjected to multivariate analysis, using logarithmic transformation to normalize the distribution of gastrin concentrations (presented as geometric means and 95%CIs). The frequency of H. pylori-positive antibody status increased with age from 28% in the second decade to >70% beyond the fourth decade. Fasting gastrin concentrations rose significantly from 44 ng/l (41–48) in the second decade to 95 ng/l (67–131) by the eighth decade (p=0.001) in the total group. Twenty-seven patients (6.8% of the total) tested positive for gastric auto-antibodies: 2% of patients in the second decade, rising to 15.9% in the eighth decade. These patients formed a distinct group with respect to circulating gastrin concentrations. Excluding these 27, fasting gastrin concentrations still rose significantly, from 44 ng/l (41–48) in the second decade, to 67 ng/l (50–89) in the eighth decade (p=0.003) in the remaining 341 patients. Fasting gastrin concentrations were significantly higher in patients who were H. pylori-seropositive (59 ng/l, 54–64 vs. seronegative 41 ng/l, 37–46) (p=0.002), and there was no increase in circulating gastrin concentrations with increasing age in either the H. pylori-positive or the H. pylori-negative group. The increase in circulating fasting gastrin observed with increasing age is due to an increased incidence of gastric antibodies associated with auto-immune atrophic gastritis, and an increased incidence of H. pylori infection.
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Introduction |
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A rise in the circulating concentrations of various regulatory peptides, including pancreatic polypeptide and gastrin, has been observed with increasing age.1–4 Circulating gastrin concentrations are elevated in patients with gastrinoma, usually to 2–100 times normal, and in antral G cell hyperfunction, where elevations are 2–20 times the upper limit of normal. Circulating gastrin concentrations are raised in other conditions including renal failure,5 phaeochromocytoma,6 post vagotomy,7 and during gastric acid suppression treatment.8,9 Circulating gastrin concentrations are also high in patients with atrophic gastritis in association with the presence of gastric parietal cell antibodies, where the acid inhibition of gastrin is absent. The incidence of gastric autoimmunity is known to increase with increasing age.10 This laboratory quotes a fasting gastrin concentration of <100 ng/l in normal control subjects11 and this is in agreement with other laboratories.12–14
Both basal and stimulated circulating gastrin concentrations are elevated in patients with duodenal ulcer disease who are also infected with H. pylori15–17 and gastrin concentrations also are raised in healthy subjects who have this infection.18,19 A high percentage of the asymptomatic population is infected with H. pylori, and the infection rate increases with age.20,21 It may be suggested therefore, that the rise in gastrin with age is entirely due to the increase in H. pylori infection and increase in gastric autoimmunity with increasing age. We investigated the relation between H. pylori, gastric autoantibodies, and age-related hypergastrinaemia.
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Methods |
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Patients
Subjects were identified from patients admitted to a general medical ward for overnight observation. Patients were interviewed, and their age and details of medical history were recorded. All patients were fasted for a minimum of 6 h prior to a single venous sample being taken on the morning of the next day. A clotted specimen (10 ml) was collected, the blood separated and the serum divided into three aliquots. One sample was processed as a routine electrolyte and creatinine block on that day. The remaining two aliquots were stored frozen at –20 °C until they were analysed: one aliquot for gastrin assay and gastric autoantibodies, the other for antibodies to H. pylori. The following exclusion criteria were applied: (i) symptoms relating to the upper GI tract; (ii) H2 receptor antagonist or proton-pump inhibitor therapy or H. pylori eradication therapy; (iii) history of pernicious anaemia; (iv) previous gastric surgery; (v) creatinine >150 mmol/l on admission. Patient diagnosis was recorded retrospectively. Approval was granted by the local Research Ethical Committee and written informed consent was obtained from each subject.
Gastric autoantibody screen
Gastric parietal cell antibody (GPCA) and antibody to intrinsic factor (IFA) were assessed in all patients who were shown to have serum gastrin concentrations above the normal range and in 25% of the remaining group (chosen randomly).
Screen for H. pylori antibodies
An enzyme immunosorbent assay (ELISA) was used to detect IgG to H. pylori. An acid glycine extracted antigen (supplied by D Newell CAMR Porton Down) was used in the method previously described by Newell.21 Subjects in whom H. pylori has been eradicated will remain seropositive for some time, thus giving a false-positive result, however no subject who had had H. pylori eradicated therapeutically was included in the study.
Serum gastrin assay
Gastrin was measured by radioimmunoassay using antibody R98 raised to synthetic human gastrin. The antiserum measures Component I, G34, G17 and G14 in both sulphated and unsulphated forms in equimolar quantities. R98 binds only C-terminally amidated gastrins, that is, only the gastrins which are associated with the stimulation of acid secretion. The sensitivity of the gastrin assay is 2 ng/l and the coefficients of variation were 7.4% inter-assay and 4.6% intra-assay.22
Statistical analysis
Data were processed using multivariate analysis. The model applied analysed gastrin concentrations using a logarithmic transformation, which normalized the distribution in all groups. Gastrin concentrations are presented as geometric means and 95% CIs.
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Results |
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We recruited 445 patients, of whom 36 were excluded because of renal impairment, and a further 43 according to the exclusion criteria, after diagnosis was established, leaving 366 for statistical analysis.
Fasting gastrin concentration rose significantly from 44 ng/l (41–48) in the second decade to 95 ng/l (67–131) in the eighth decade (p=0.001) (Figure 1
). Of the 366 patients, 67.2% were H. pylori-positive. H. pylori seropositivity increased with age (p=0.002), from 28% in the second decade, to 43.3% in the third decade and 72.5% in the fourth decade. From the fifth decade, the infection rate remained between 70% and 80% (Figure 2).
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Thirteen patients (3.6%) had serum gastrin concentrations >1000 ng/l. These patients were recalled, and blood specimens were analysed for GPCA, IFA and a full blood picture. All 13 had gastric autoantibodies, with a megaloblastic anaemia, and all have commenced vitamin B12 replacement therapy. A further 68 (18.6%) had gastrin concentrations above the normal range (>100 ng/l and <1000 ng/l). Of these patients, 12 tested positive for the presence of either GPCA or IFA. Two other patients who had gastrin concentrations within the reference range were positive with respect to gastric autoantibodies. The gastric autoimmune subjects represent 7.4% (9.0% adjusting for the sample taken) of the total group. Of the patients who were gastric-autoantibody-positive, 44% were also seropositive for H. pylori. The percentage of patients with autoantibodies as described above was 2.0% in the second decade increasing to 15.9% in the eighth decade (Figure 3
). Analysis showed no interaction between the presence of GPCA/IFA and H. pylori seropositivity.
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Circulating gastrin concentration was positively correlated with age in the patients who did not have gastric autoantibodies. Gastrin rose significantly from 44 ng/l (41–48) in the second decade to 67 ng/l (50–89) in the eighth decade (p=0.003).
Circulating gastrin concentrations and H. pylori antibody status were compared in these 341 patients. The mean fasting serum gastrin concentration in patients who were H. pylori-seropositive was 59 ng/l (54–64), significantly higher than in H. pylori-seronegative patients who had a (41 ng/l, 37–46) (p=0.002).
Multivariate analysis showed that, with respect to circulating gastrin concentration, the population studied fell into three groups. Patients who were GPCA/IFA-positive had mean circulating gastrin concentrations of 724 ng/l (446–1176) and were significantly different to both the H. pylori-seropositive group (59 ng/l, 54–64) and the H. pylori-seronegative group (41 ng/l, 37–46) (Table 1). All three groups were significantly different from each other, and no group showed any correlation between circulating gastrin concentration and age.
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Discussion |
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A considerable number of our patients had undiagnosed pernicious anaemia, and in total 31% of the patients who had gastrin concentrations outside the normal range were GPCA- or IFA-positive. In our patient population, 56 (15.3%) recorded circulating gastrin concentrations above the normal range and did not have gastric autoimmunity.
We have shown a 46% increase in geometric mean fasting serum gastrin concentrations in the patients who tested seropositive for H. pylori antibody. This equates to 67% using an arithmetic mean, and is in keeping with other published data.16–18
The present survey shows a somewhat higher rate of seropositivity for H. pylori antibody than has generally been reported in developed countries. This may reflect a bias in the socio-economic class of subjects in the geographic sample area. This high rate of infection shown, however, substantiates data relating to the incidence of H. pylori infection in children in Northern Ireland,25 which may add evidence to the suggestion that H. pylori infection rates are indeed high in this province. Serological tests for H. pylori antibody will give a positive result for some time after eradication, therefore if any the patients had undergone eradication they would have appeared as false positives. None of the subjects had undergone therapeutic H. pylori eradication. Although it had originally been thought that H pylori would not persist in the stomach in the absence of gastric acid, this has been shown not to be the case. H. pylori infection spreads throughout the body of the stomach when acid secretion is low or absent, and can persist.26
It is established that fasting gastrin concentrations increase with age.3,14,27,28 The present study clearly illustrates that circulating gastrin concentrations increase with age due only to two complicating factors. First, the incidence of GPCA and IFA increases with increasing age, producing a considerable elevation in serum gastrin concentration, which we have shown. Second, the incidence of H. pylori infection increases with age, and this is also accompanied by an elevation in circulating gastrin concentrations. We found no rise in circulating gastrin concentrations in the absence of these two factors. One might expect some evidence of rises in circulation gastrin concentration in the older patients due to gastric body atrophy which may occur in some patients. This would result in hypochlorhydria or achlorhydria, and would therefore be accompanied by an increase in circulating gastrin. There was no evidence of this in the present study.
We conclude therefore that the increase in circulating fasting gastrin concentration observed with increasing age is due to the increased incidence of gastric autoantibodies and an increasing incidence of H. pylori infection, and that there is no rise in gastrin with increasing age per se.
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Acknowledgments |
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The authors wish to thank Michael Stevenson (Statistician), Health and Health Care, QUB, for expert statistical advice.
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References |
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