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Original Studies |
Gastroenterology Unit 1 (A.M., C.G., S.C., G.D.F., B.A.), Internal Medicine IV (S.M., C.D., G.S.), Semeiotica Chirurgica IV (G.D.A.), and Department of Cellular Biotechnology and Haematology (V.D.C., R.S.), University La Sapienza, 00161 Rome; and Department of Pathology (C.B.), University of Parma, 43100 Parma, Italy
Address correspondence and requests for reprints to: Gianfranco Delle Fave, M.D., Cattedra di Gastroenterologia, Dipart.Di Medicina Clinica, Policlinico Umberto I, 00161 Rome, Italy. E-mail: dddhgi{at}tin.it
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In view of these relatively new insights, the aim of the present study was to determine the prevalence of increased fasting serum gastrin levels in a group of consecutive PHPT patients and to examine all the known factors causing hypergastrinemia. Appropriate diagnostic procedures able to elucidate the different clinical and biochemical findings were carried out.
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Subjects and Methods |
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Fifty-two consecutive patients with primary PHPT [42 female
(F), 10 male (M)], age median 65 yr (range, 24–78) were investigated
from 1992 to 1997 (Table 1
), before
surgical treatment for hyperparathyroidism. Diagnosis of PHPT was
established on the basis of elevated serum levels of PTH and ionized
calcium. Patients with gastric stenosis, previous gastric vagotomy, or
renal function impairment were excluded from the study, because these
conditions could determine an increase of circulating gastrin levels
(11). Written consent was obtained from the subjects after they were
informed that further investigations related to the primary
hyperparathyroidism were not necessary . The research protocol was
approved by the local (University La Sapienza, Rome) ethical committee
in adherence with the Declaration of Helsinki.
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Basal fasting gastrin levels were determined in all patients. PHPT patients with increased basal gastrin levels (normal values < 40 pg/mL) were further investigated with basal and pentagastrin-stimulated gastric acid secretion (PAO) evaluation and secretin provocative test. Upper gastrointestinal endoscopy with multiple gastric biopsies was also performed in all patients that completed the study, either to confirm the diagnosis of GFA or Helicobacter pylori gastritis or to assess the H. pylori status.
Patients were also carefully questioned to elicit a personal and/or family history of peptic disease or presence of endocrine disorders. Moreover, patients on gastric antisecretory treatment, either on histamine H2-receptor antagonists or proton pump inhibitors (PPIs), were asked to stop taking drugs for 7 days before the tests were carried out, to eliminate any increasing influence on gastrin plasma levels (12).
Methods
Biochemical measurements and histological evaluation. Metabolic tests included a 24-h urine collection, followed by a short urine collection (from 0800 h to 1100 h) after a 12-h overnight fast. At the same time, a blood sample was taken to determine the main parameters of calcium metabolism, according to previously described methods (13). Normal values of these biochemical variables are: total serum Ca++, 8.60–10.50 mg/dL; serum ionized Ca++, 1.17–1.33 mmol/dL; total serum alkaline phosphatase activity, 39–111 U/L; serum creatinine, 0.6–1.4 mg/dL; and serum PTH, 10.6–54 pg/mL (13) .
Basal acid secretion (BAO) and PAO, i.e. after 6 µg pentagastrin (Peptavlon, Zeneca Pharmaceuticals, Alderley Edge, England) injected sc, were determined as previously described (14). The BAO/PAO ratio was also calculated. Normal values are: BAO, 1–11 milliequivalent/h; PAO, 4–44 milliequivalent/h; and BAO/PAO < 0.3 (12).
Plasma gastrin was evaluated by means of specific RIA, using antibody no. 4562 (J. F. Rehfeld), as previously described (15). Basal gastrin values represent the mean value of two basal samples (expressed as pg/mL) equivalent to human gastrin-17. Normal basal gastrin values in our laboratory are: 10–40 pg/mL. A secretin test was carried out as follows: 2 UI/kg·bolus of human synthetic secretin (Bachem AG, Bubendorf, Switzerland) was administered iv, and blood samples were collected at 5-min intervals for 30 min. A gastrin increment more than 200 pg/mL above basal values was considered positive for Zollinger Ellison Syndrome (ZES) (12). Upper gastrointestinal endoscopy was performed with the use of a fiber optic GIF XQ10 gastroscope (Olympus Corp. Optical Co. Hamburg, Germany). Three biopsies from the midpart of the gastric body mucosa and three biopsies from the antral mucosa were obtained from each patient. Biopsies were fixed in Bouin’s fluid for 4–5 h at room temperature. After rinsing in 70% ethanol, they were alcohol-dehydrated and embedded in paraffin. All biopsy specimens were processed as previously described (16), and the degree of gastritis was performed according to the Sydney system (17).
Statistical evaluation. The distribution of basal data (both gastrin and acid secretion) failed to fit into a Gaussian curve. Data were expressed as median range and were evaluated by nonparametric statistical tests (Mann Whitney-Wilcoxon rank tests). P < 0.05 was considered as statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). The remaining 32 PHPT patients had
normal gastrin values; median, 20 pg/mL (10–40 range). There was a
nonsignificant statistical difference between normo- and
hypergastrinemic PHPT patients regarding ionized calcium and PTH
levels, age and sex distribution, and prevalence of kidney stones
disease (Table 1). The final diagnosis was mostly adenomas in both
groups of surgically treated patients (Table 1). Only adenomas showed
normal calcium levels at the postsurgery control (data not shown).
Furthermore, no correlation was found between calcium and gastrin
levels, either considering all consecutive PHPT patients or the
hypergastrinemic PHPT patients alone (r of -0.218, P
< 0.119; and r of -0.315, P < 0.174; respectively).
Upper gastrointestinal symptoms, such as epigastric pain and/or pyrosis
and/or dyspepsia (i.e. mild upper gastrointestinal
discomfort) were present in 12 out of the 20 hypergastrinemic PHPT
patients (60%), compared with 31% of symptomatic PHPT
normogastrinemic patients (P < 0.05) (Table 1).
Further investigations, assessing causes of hypergastrinemia, led to
the diagnosis of GFA in 7 patients (35%). They had basal and
stimulated hypoachlorhydria and negative secretin tests, with diagnosis
confirmed by gastric mucosal histology (Table 2). ZES with MEN-I was found in 3
hypergastrinemic patients (15%). Two of these patients had an
increased BAO and BAO/PAO ratio and epigastric pain and/or diarrhea,
with positive secretin test (Table 2). Endoscopy revealed a duodenal
ulcer in 2 of these patients and mild esophagitis in the other patient.
In these 3 patients, gastrinomas were also localized with specific and
sensitive imaging studies, magnetic resonance imaging, and somatostatin
receptor scintigraphy.
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) (Table 2).
Four PHPT patients (20%) (Table 2) had normal basal and stimulated
gastric acid secretion (Fig. 1), combined with antral gastritis,
presence of Helicobacter pylori and hypergastrinemia. The
mild hypergastrinemia in these four PHPT patients was attributable to
the H. pylori infection, because serum gastrin
values decreased to the normal range after an eradication treatment for
H. pylori. In the two other patients, the
hypergastrinemia was attributable to the ingestion of PPIs taken
for occasional epigastric pain at the time of the gastrin analysis
(Table 2), as demonstrated by the fact that subsequent sampling
revealed normal gastrin levels (data not shown). During the study, one
patient died from aggressive parathyroid cancer, and three other
patients refused further investigations. However, the mild fasting
hypergastrinemia in all four patients made the presence of ZES or GFA
in these patients unlikely (Table 2).
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Discussion |
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The normogastrinemic and hypergastrinemic PHPT patients could not be distinguished, either by their PTH and Ca++ basal levels or the prevalence of history of kidney stone disease. In contrast, hypergastrinemic patients, more frequently than normogastrinemic PHPT patients, complained of upper gastrointestinal symptoms [60% vs. 31% (P < 0.05)]. It has been reported that more than 90% of patients with MEN 1 develop hyperparathyroidism, and a ZESlinger-Ellison syndrome is associated in up to 54% of them. Three patients (15%) had MEN 1 with gastrinoma as a cause of the hypergastrinemia; this diagnosis can be difficult to establish in some patients. In the present study, the increase of serum gastrin after secretin infusion was less than 200 pg/mL in 1 patient with a proven ZESlinger-Ellison syndrome with MEN-I. Although the secretin test is considered highly specific and sensitive for the diagnosis of ZES, up to 13% of patients with proven gastrinoma have an unexplained negative secretin test (19). In one study (20), a negative secretin provocative test was reported to be present among PHPT patients with ZES/MEN-I. The basal and stimulated hypoachlorhydria, as well as a negative secretin test, suggested the diagnosis of GFA in 35% of the hypergastrinemic PHPT patients. This diagnosis was confirmed in all these patients, with histology, which demonstrated various degrees of atrophy in the acid secretory mucosa and chronic inflammation. Although GFA has been previously reported to cause hypergastrinemia in PHPT patients (4), very few studies are available in which the diagnosis of GFA was made on the basis of both functional and histological gastric evaluations. Both aspects are mandatory, to make a correct diagnosis of GFA (21, 22). Serum gastrin basal levels overlapping between patients with ZES/MEN-1 and those with GFA and, therefore, could not be used to distinguish between these two very different conditions. Gastric acid determination, although invasive and unpleasant for the patient was, however, a simple and highly specific method to differentiate these two conditions as a cause of hypergastrinemia in patients with PHPT.
It has been reported that basal gastric hypoachloridria in a patient with mild hypergastrinemia could be temporary, attributable to H. pylori gastritis (10). In such cases, a recovering of normal fasting gastrin levels and gastric secretion is frequently seen after H. pylori eradication (10). In 4 out of 20 hypergastrinemic PHPT patients, all with mild hypergastrinemia and basal gastric hypoachlorhydria, active H. pylori gastritis was found upon histological examination. The presence of an H. pylori infection gives a reasonable explanation for some of the previous unexplained cases of mild hypergastrinemia in PHPT patients (2, 4). Thus, an H. pylori investigation should be included in the evaluation of mild hypergastrinemia (<160 pg/mL) in PHPT patients before more invasive and expensive tests, such as the secretin test or gastric acid secretion evaluation, are carried out.
In two patients, an additional detailed clinical history showed a recent occasional use of the potent gastric acid secretion inhibitory drug (omeprazole). Numerous studies (23, 24) have demonstrated that treatment with PPIs can result in hypergastrinemia, because of their long duration of action. The effects of gastric PPIs can last several days after their discontinuation and the hypoachlorhydria caused by these kinds of drugs is sufficient to activate the acid/gastrin secretory negative feedback (25).
This study: 1) demonstrates that hypergastrinemia in PHPT patients can almost always be clearly ascribed to a specific cause; and 2) does not support the hypothesis that the PHPT condition alone can determine an increase of circulating gastrin levels. This has been confirmed also by the lack of correlation between circulating calcium and gastrin levels, either in all PHPT patients or, at least, in the hypergastrinemic PHPT patients observed in this study. Even if we still do not know how the fasting gastrin level can be in PHPT patients with very high ionized calcium levels, in our PHPT patients with mild/moderate ionized calcium, gastrin hypersecretion is attributable to the presence of a specific condition which per se causes an increase of fasting gastrin levels. Furthermore, this study shows that hypergastrinemia in PHPT patients is most frequently caused by nontumoral conditions, such as atrophic fundus and H. pylori gastritis.
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Acknowledgments |
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Footnotes |
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Received March 25, 1999.
Revised June 3, 1999.
Accepted August 30, 1999.
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References |
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