Helicobacter pylori related hypergastrinaemia is the result of a selective increase in gastrin 17

Helicobacter pylori infection increases the serum concentration of gastrin, and this may be one of the mechanisms by which it predisposes to duodenal ulceration. Different forms of circulating gastrin were studied both basally and postprandially in 13 duodenal ulcer patients before and one month after eradication of H pylori. Three antisera that are specific for particular regions of the gastrin molecules were used. Gel chromatography indicated that > 90% of the circulating gastrin consisted of gastrin (G) 17 and G34 both before and after eradicating the infection. The basal median total immunoreactive gastrin concentration fell from 26 pmol/l (range 11-43) to 19 pmol/l (8-39) (p < 0.05), entirely because of a fall in G17 from 6 pmol/l (< 2.4-25) to < 2.4 pmol/l (< 2.4-23) (p < 0.001). The median (range) basal G34 values were similar before (15 pmol (2-36)) and after (10 pmol (2-30)) eradication. The median total immunoreactive gastrin concentration determined 20 minutes postprandially fell from 59 pmol/l (38-114) to 33 pmol/l (19-88) (p < 0.005), and again this was entirely the result of a fall in G17 from 43 pmol/l (9-95) to 17 pmol/l (< 2.4-52) (p < 0.001). The median postprandial G34 values were similar before (13 pmol/l, range 6-42) and after (15 pmol/l, range 6-30) eradication. Eating stimulated a noticeable rise in G17 but little change in G34, both in the presence and absence of H pylori. The finding that H pylori infection selectively increases G17 explains why the infection causes mainly postprandial hypergastrinaemia. G17 is increased selectively because H pylori predominantly affects the antral mucosa which is the main source of G17 whereas G34 is mainly duodenal in origin. This study also indicates that the increased concentration of gastrin in H pylori infection is the result of an increase in one of the main biologically active forms of the hormone.     

Evaluation of two commercial kits for serum gastrin assay, and comparison with a conventional radioimmunoassay procedure

We compared two gastrin radioimmunoassay kits ("Immutope" kit, Squibb & Co.; "Gastrin R.I.A." kit, Schwarz/Mann) to the conventional gastrin radioimmunoassay of Yalow and Berson [Gastroenterology 58, 1 (1970)] as run by us and by a second reference laboratory. Although both kits were found to effectively discriminate above-normal and normal values for serum gastrin, they significantly underestimated very high values (greater than 1500 ng/liter). The Schwarz/Mann kit clearly had a superior quality label (lower nonspecific binding and higher specific activity) and a shorter incubation time. However, the 90-min incubation period cited for their kit caused overestimation of gastrin values in the lower range (5-300 ng/liter), which could be corrected by prolonging the incubation to 24 h. The Squibb antibody had fairly good cross reactivity to all gastrin species tested; the Schwarz/Mann antibody had poor affinity for natural human gastrin G34-II. Good correspondence was found for sera run by both reference laboratories (y = 0.96x + 10, r = 0.997), and values obtained with the Schwarz/Mann kit correlated best (+ 0.815) with those from the conventional radioimmunoassay procedure.     

Biological activity of carboxy-terminal gastrin analogs

Amidated forms of gastrin are derived by post-translational processing of a large precursor peptide and stimulate gastric acid secretion via the gastrin/CCK(B) receptor. Non-amidated biosynthetic intermediates may exert biological effects through other mechanisms, but their effect on gastric acid secretion is unclear. Amidated gastrins stimulate acid secretion mainly by releasing histamine from mucosal enterochromaffin-like cells. This study examines the effects on histamine release from the vascularly perfused rat stomach of amidated gastrin-17, COOH-terminal glycine-extended gastrin-17, gastrin-17 extended at the COOH-terminal including the remaining progastrin sequence, and carboxy-terminal progastrin fragments (SAEDEN and GRRSAEDEN). Carboxy-terminal extended gastrins induced histamine release which was inhibited by the gastrin/CCK(B) antagonist L-740,093, but had to be given in concentrations 100-fold higher than amidated gastrin-17 to produce comparable effects. These progastrin-derived peptides are found in high concentrations in some patients with the Zollinger-Ellison syndrome and may contribute to acid hypersecretion and other gastrin/CCK(B) receptor mediated responses.     

Effect of intrajejunal fat on meal-stimulated acid and gastrin secretion in man

The effect of intrajejunal fat infusion on meal-stimulated gastric acid and gastrin secretion was studied in 8 healthy volunteers. Intrajejunal fat significantly reduced the acid response to a meal, measured by intragastric titration, as compared to intrajejunal infusion of saline. While serum gastrin concentrations rose from fasting levels to a constant plateau after the meal when saline was infused, fat infusion resulted in a transitory decrease in serum gastrin concentration followed by a significant increase. It is concluded that inhibition of gastrin release only plays a minor role, if any, in the observed fat-induced jejuanl inhibition of meal-stimulated acid secretion.     

The role of the beta-adrnergic receptor in the secretion of gastrin: studies in normal subjects and in patients with duodenal ulcers

Intravenous infusion of isoproterenol, a beta-adrenergic receptor stimulatory agent, increased serum gastrin concentration significantly more in patients with a duodenal ulcer than in healthy subjects. The rise in pulse rate, blood glucose concentration and in serum insulin was the same in both groups of subjects. Gastrin secretion was also increased significantly more in the patients than in the control subjects after a beef-meal. Basal serum gastrin concentrations were higher in the patients than in the control subjects and correlated to the rise in serum gastrin during both tests in the patients with a duodenal ulcer. Isoproterenol and meal stimulated gastrin secretion, expressed as percent of the basal value, were twice as higher in the patients as in the control subjects. The combined administration of isoproterenol and the meal had an additive effect on the rise in serum gastrin. Isoproterenol stimulated gastrin secretion was completely suppressed by propranolol, a beta-adrenergic receptor blocking agent, which had no effect on meal stimulated gastrin secretion. It is concluded that the mechanism of the hypersecretion of gastrin in patients with a duodenal ulcer did not involve a specific abnormality of the beta-adrenergic receptor or the receptor which recognized proteins and their digested products. There is no established role of beta-adrenergic receptor activity in the hypersecretion of gastrin in patients with duodenal ulcers. It is suggested that the beta-adrenergic receptor may have some yet unknown function unrelated to the acute secretory response of gastrin.     

Inhibition of omeprazole induced hypergastrinaemia by SMS 201-995, a long acting somatostatin analogue in man

Whether the long acting somatostatin analogue SMS 201-995 (octreotide, Sandostatin) could inhibit the basal and meal stimulated hypergastrinaemia and hyperpepsinogenaemia induced by omeprazole was investigated. Eight healthy subjects were randomised to receive five day courses of SMS 201-995 (25 micrograms subcutaneously three times daily), omeprazole (40 mg once a day), a combination of both drugs, or placebo. Basal and meal stimulated serum gastrin and basal serum pepsinogen A and C values were measured the day before treatment, on day five of treatment, and the day after each course of treatment. Omeprazole caused significant increases in basal and meal stimulated peak and integrated serum gastrin values and pepsinogen A and C levels, which were still significantly raised the day after stopping omeprazole treatment. Giving SMS 201-995 with omeprazole significantly reduced any omeprazole induced increases in basal and meal stimulated peak and integrated serum gastrin levels; serum pepsinogen A and C values were significantly inhibited too. Serum gastrin values during combined therapy were not significantly different from those during placebo treatment, whereas pepsinogen A and C levels were still significantly raised. On the day after stopping combined therapy, basal and meal stimulated peak and integrated serum gastrin and serum pepsinogen C (but not pepsinogen A) levels were not significantly different from values obtained on the day after stopping omeprazole alone. SMS 201-995 without omeprazole significantly inhibited basal and meal stimulated peak and integrated serum gastrin levels. Pepsinogen A was also significantly inhibited by SMS 210-995, but the reduction in pepsinogen C failed to reach statistical significance. In conclusion, SMS 201-995 prevents basal and meal stimulated increases in serum gastrin during omeprazole therapy. This finding may have clinical importance in the few patients who have pronounced hypergastrinaemia because of profound long acting acid inhibition.     

Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha

BACKGROUND: In patients with louse-borne relapsing fever (Borrelia recurrentis infection), antimicrobial treatment is often followed by sudden fever, rigors, and persistent hypotension (Jarisch-Herxheimer reactions) that are associated with increases in plasma concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6, and interleukin-8. We attempted to determine whether sheep polyclonal Fab antibody fragments against TNF-alpha (anti-TNF-alpha Fab) could suppress the Jarisch-Herxheimer reaction. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in 49 patients with proven louse-borne relapsing fever. Immediately before the intramuscular injection of penicillin, the patients received an intravenous infusion of either anti-TNF-alpha Fab or a control solution. RESULTS: Ten of the 20 patients given anti-TNF-alpha Fab had Jarisch-Herxheimer reactions with rigors, as compared with 26 of the 29 control patients (P = 0.006). The controls had significantly greater mean maximal increases in temperature (1.5 vs. 0.8 degrees C, P < 0.001), pulse rate (31 vs. 13 per minute, P < 0.001), and systolic blood pressure (25 vs. 15 mm Hg, P < 0.003), as well as higher mean peak plasma concentrations of interleukin-6 (50 vs. 17 micrograms per liter) and interleukin-8 (2000 vs 205 ng per liter) (P < 0.001 for both comparisons). Levels of TNF-alpha were undetectable after treatment with anti-TNF-alpha Fab. CONCLUSIONS: Pretreatment with sheep anti-TNF-alpha Fab suppresses Jarisch-Herxheimer reactions that occur after penicillin treatment for louse-borne relapsing fever, reduces the associated increases in plasma concentrations of interleukin-6 and interleukin-8, and may be useful in other forms of sepsis.     

The place of gastrin determination in ulcer surgery

This paper is concerned with the place of gastrin determination in ulcer surgery. Only the acid-stimulating properties of gastrin are considered. The role of the vagus in the gastrin response to a test meal was investigated in patients with duodenal ulcer. 50 patients were studied before and 3, 6, and 12 months after highly selective vagotomy without (25 patients) and with Wnagensteen-pyloroplasty (25 patients). Basal and stimulated gastrin concentration in serum, as determined by radioimmunoassay, were higher 3 months after the operation and 3h after the test meal gastrin levels were still 50% higher than the basal levels. No difference was found between the patients treated with highly selective vagotomy and the patients treates with HSV and additional pyloroplasty. 6 and 12 months after the operation a moderate decrease of gastrin secretion was observed, but basal as well as stimulated levels were still elevated after 12 months compared to the values before operation. Our results indicate that the pattern of gastrin secretion changes as time passes after highly selective vagotomy with or without additional pyloroplasty.     

Effect of gastrin-17 on lower esophageal sphincter characteristics in man

We studied the effect of gastrin-17 on lower esophageal sphincter (LES) characteristics in man. Nine healthy volunteers participated in two experiments performed in random order during continuous infusion of saline (control) or gastrin-17 (15 pmol/kg/hr). LES pressure (LESP) and transient lower esophageal sphincter relaxations (TLESR), as most the important reflux mechanism, were measured with intraesophageal sleeve manometry combined with pH metry. Infusion of gastrin-17 resulted in plasma gastrin levels comparable to those reached after a mixed meal. During continuous gastrin infusion, LESP decreased significantly (P < 0.05) compared to control. The rate and duration of TLESR was not influenced by gastrin-17. Gastroesophageal reflux and the number of TLESR associated with reflux were significantly (P < 0.05) increased during gastrin infusion. These results suggest that in humans gastrin at physiological postprandial plasma concentrations decreases LESP, does not influence TLESR, but increases the percentage of TLESR associated with reflux.     

Gastrin-17 and G17-gly induce proliferation of LoVo cells through the CCK B/gastrin receptor

BACKGROUND AND METHODS: Recent studies suggest that glycine-extended gastrin (G17-gly) stimulates in vitro proliferation of the pancreatic cell line AR4-2J, through selective receptors distinct from the CCK-B/G-receptor mediating the effects of amidated gastrin (G17). The aims of our study were to examine the effects of G17 and G17-gly on the growth of the colorectal cancer cell line LoVo and to determine the receptor involved by using selective receptor-antagonist. RESULTS: Both G17 and G17-gly stimulated [3H]-thymidine incorporation in a concentration-dependent fashion. Maximal stimulation (153 +/- 18% and 166 +/- 17% of control, p < 0.01) was achieved with 10 nM G17 and 100 nM G17-gly, respectively. These stimulations were fully prevented by the presence of 10 pM YM022, a G/CCK B receptor-antagonist, but unaffected by L364,718, a CCK A receptor-antagonist. Basal growth of LoVo cells was inhibited by YM022 and stimulated by L364,718. CCK A and G/CCK B receptors mRNA were detected in the cells. Gastrin immunoreactivity was detected in the cells (16 pM) and in the extracellular medium (4.5 pM). CONCLUSION: Both G17 and G17-gly stimulate LoVo cells growth through the activation of a gastrin/CCK B receptor. The evidence for secreted gastrin and CCK A and B receptors mRNA may further suggest the existence of an autocrine loop involving a stimulatory gastrin/CCK B receptor.     

SarA level is a determinant of agr activation in Staphylococcus aureus

Shortage of reliable plasma assays has hampered studies of cholecystokinin (CCK). The assay problems are low plasma concentrations, extensive molecular heterogeneity, and close homology of CCK to gastrin, which circulates in higher concentrations. To develop an accurate CCK RIA, antibodies were raised in rabbits, guinea pigs, and mice in titers from 200 to 4000000. The specificity of the antisera was tested with homologous peptides, and tissue and plasma extracts. Rabbit 92128 produced antibodies in high titer (> or =500000) with sufficient avidity (K(o)eff > or = 10(12) mol(-1)) and the desired specificity. The antiserum binds the bioactive forms of CCK with equimolar potency and displays no reactivity with gastrin. CCK concentrations in plasma from healthy humans rose from 1.13 +/- 0.10 pmol/L (mean +/- SE, n = 26) to 4.92 +/- 0.34 pmol/L after a mixed meal. Chromatography of human plasma revealed traces of CCK-58, a predominance of CCK-33 and CCK-22, and moderate amounts of CCK-8. The results show that it is possible to produce specific CCK-antisera using a sulfated CCK-12 analog.     

Molecular forms of gastrin in antral mucosa, plasma and gastric juice during vagal stimulation of anesthetized cats

Gastrin was released by electrical vagal stimulation in anesthetized cats. Antral mucosa, blood and gastric juice samples collected during vagal stimulation were subjected to gel filtration in order to characterize the different molecular forms of gastrin. In antral mucosa component III (gastrin-17) predominated. Besides, the antrum contained 5 per cent component II (gastrin-34, "big" gastrin), 1 per cent component I and trace amounts of component IV (gastrin-14 or "mini" gastrin). Immediately after vagal stimulation, component III (gastrin-17) appeared in the gastric venous effluent followed within a few minutes by component IV (gastrin-14). Component I and II (gastrin-34) were not detectable in any of the plasma samples. We suggest that component III (gastrin-17) is released from the antral mucosa and is then rapidly metabolized to component IV (gastrin-14) possibly to a significant extent in the fundic region of the stomach. Large amounts of component III (gastrin-17) were found in the vagally-induced gastric juice. Only very small amounts of degradation products were present, indicating that cat gastrin is relatively resistant to peptic degradation and acid hydrolysis.     

Serum gastrin I concentrations of mother and newborn immediately after birth

Serum gastrin I (GLU-GLY-PRO-TRYP-LEU(GLU)6-ALA-[formula, see text]-GLY-TRY-MET-ASP-PHE-CO-NH2) concentrations were investigated by radioimmunoassay in 50 mothers and their newborn infants immediately after birth. The mean serum gastrin concentration in maternal blood was 52.80 +/- 13.37 (SD) pg/ml, and in cord blood 84.12 +/- 42.90 (SD) pg/ml. Both values were significantly higher than serum gastrin levels found in normal, healthy, nonpregnant women (Mean +/- SD = 32.34 +/- 18.35 pg/ml). There were no statistically significant differences in the cord serum gastrin concentrations with respect to sex, weight and length of the infant and age and parity of the mother.     

Serum gastric concentration after sham feeding and feeding under the influence of propranolol in man

The influence of propranolol, 50 mug/kg administered intravenously, on the gastrin concentration during sham feeding and after a test meal was studied in eight normal subjects. beta-Adrenergic blockade had no inhibitory effect on the gastrin response to feeding. Sham feeding did not provoke a significant rise of serum concentration; however, in three subjects a definite gastrin response occurred in the presence of beta-adrenergic blockade.     

Influence of long-term human recombinant erythropoietin treatment on secretion of pancreatic polypeptide and gastrin in hemodialysed patients with chronic renal failure

The study aimed to assess the influence of long-term rhu-EPO treatment on secretion of pancreatic polypeptide (PP) and gastrin. A total of 27 haemodialysed patients and nine healthy subjects were examined. Nine patients with uraemic anaemia were treated with rhu-EPO for 12 months (EPO group), while another nine patients did not receive rhu-EPO (non-EPO group), but were monitored biochemically and clinically as patients of the EPO group. The third group (HD) comparised nine haemodialysed patients with a haematocrit value > or = 30% without rhu-EPO therapy. In all subjects plasma levels of PP and gastrin were estimated before and after administration of a test meal. Patients of the EPO and non-EPO group were examined before and after 6 and 12 months of rhu-EPO therapy (EPO group) or clinical monitoring (non-EPO group) respectively, while only one test was performed in patients of the HD group and healthy subjects. Six months rhu-EPO therapy was followed by an decrease of basal plasma level of PP and increased response of gastrin to the test meal. After 12 months of rhu-EPO therapy basal plasma level of PP was still lower, the response of PP secretion to a test meal was higher, while that of gastrin secretion lower that the pretreatment ones. Our results suggest, that rhu-EPO treatment exerts effect on secretion of PP and gastrin. These alterations seem not to be related to improvement of the haematological status.     

Does Helicobacter pylori-induced gastritis enhance food-stimulated insulin release?

The fact that H. pylori gastritis results in an increased secretion of basal and meal-stimulated gastrin, which is also a physiologic amplifier of insulin release directed us to investigate whether H. pylori gastritis may lead to an enhancement of nutrient-stimulated insulin secretion. For this purpose, we have investigated the insulin responses to both oral glucose and a mixed meal in 15 patients with H. pylori gastritis before and one month after the eradication therapy and also in 15 H. pylori-negative control subjects. The areas under the curve (AUC) for serum insulin following both oral glucose and a mixed meal in the patients with H. pylori gastritis before the eradication were significantly (P < 0.05) higher than those in the H. pylori-negative controls. After the eradication of H. pylori, the AUC for serum insulin following oral glucose and mixed meal decreased by 9.4% and 13.1%, respectively (P < 0.001 in both), and serum basal and meal-stimulated gastrin levels decreased significantly (P < 0.001). These results suggest that H. pylori gastritis enhances glucose and meal-stimulated insulin release probably by increasing gastrin secretion.     

Association between serum gastrin levels, gastric acid secretion and age in early gastric cancer

This study evaluated the effect of gastric acid secretion and serum gastrin response on tumor differentiation for early gastric cancer according to patients' age. We investigated the association between serum gastrin levels, gastric acid secretion and the histologic types of 335 early gastric carcinomas limited to the mucosal and submucosal layers in comparison with 450 gastric and 197 duodenal ulcers. The preoperatively examined basal acid output, maximal acid output and peak acid output after administration of tetragastrin and serum gastrin levels before and after ingestion of a test meal were determined. Patients with differentiated cancer and duodenal ulcer showed a significant negative correlation between gastric acid secretion and age, while the former group also had a significant positive correlation between serum gastrin levels and age. On the other hand, patients with undifferentiated cancer did not show any such correlation between gastric acid and age, but showed a significant positive correlation between serum gastrin, integrated gastrin response and age. Patients with gastric ulcer did not show any such correlations. These data suggest that both low acid secretion and endogenous hypergastrinemia, especially in the elderly, may play an important role in differentiated and undifferentiated gastric carcinomas.     

Humoral immunostimulation. VIII. Increased incorporation of phosphate and turnover of phosphatidylinositol in cells treated with antibody

Uptake of phosphate (32P) in L cells was modulated by reaction with anti-L cell antibody. A biphasic response was noted with high, cytotoxic concentrations inhibiting 32P uptake and low, cytostimulatory concentrations stimulating 32P uptake. Stimulation of 32P uptake was dependent upon multivalent binding as immune IgG and F(ab')2 were effective, but univalent Fab' was ineffective in enhancing 32P uptake into cells. Antibody stimulation of 32P uptake appeared to be an energy independent process and to take place by activation of 32P membrane transport with an increased Vmax (19.3 pmoles/min to 25.3 pmoles/min), but the same Km (0.22 mM). Isolation and measurement of cellular (primarily membrane) phospholipids demonstrated a dramatic increase of (2-fold) specific radioactivity in phosphatidylinositol. Early turnover of phosphatidylinositol may be an important signal for tumor cells to grow at an enhanced rate when exposed to cytostimulatory concentrations of antibody.     

Fibronectin in tissues and saliva of patients with oral lichen planus

BACKGROUND: Whilst gastrin has been found to be trophic for some colorectal cancer cell lines, and gastrin receptor antagonists are able to block this phenomenon, their potency has been modest. METHODS: The effect of a new, potent and selective CCK B receptor antagonist, CI-988 on the growth of LoVo, a human colon cancer cell line both in vitro and in vivo was instigated. RESULTS: Basal growth of LoVo in vitro was inhibited by up to 58.93 +/- 7.30% with concentrations of CI-988 as low as 1 X 10(-11) mol/L whereas the addition of gastrin (G17) at 0.5 nmol/L had no effect. LoVo was also grown in vivo for 10 days in nude mice subsequently treated with CI-988 at 10 mg/kg per day orally for 20 days. CI-988 inhibited the growth of xenografts by 53%. CONCLUSION: This was the first study in cancer with this potent gastrin receptor antagonist, CI-988. The results suggest that CI-988 may be of use in inhibiting the growth of colorectal cancer.     

Malaria in the southern sanitary district of Dakar (Senegal). 2. Entomologic data]

This study aimed to investigate the cause of persistently increased serum gastrin concentration seen in some Graves' disease patients even when euthyroid during antithyroid drug treatment. The subjects studied consisted of three groups: 33 patients with a common-type of Graves' disease, 14 with triiodothyronine (T3)-predominant Graves' disease (characterized from previous studies as having potent immunologic abnormalities including greater concentrations of thyroid-stimulating antibodies together with larger goiter size), and a group of 20 normal subjects. Fasting serum gastrin concentrations in common Graves' disease patients were significantly higher than those of normal subjects (58.4 +/- 38.9 pmol/L vs. 37.8 +/- 18.9 pmol/L [mean +/- SD], p < 0.05). The serum gastrin concentrations were even greater in T3-predominant Graves' disease patients than common Graves' disease patients (162.9 +/- 224.0 pmol/L vs. 58.4 +/- 38.9 pmol/L, p < .05). Serum pepsinogen I (PGI) concentrations were significantly lower in the T3-predominant patient group than the common Graves' group (24.0 +/- 12.9 ng/mL vs. 39.7 +/- 19.6 ng/mL, p < .05). Serum ratios of PG I to PG II were significantly lower in the T3-predominant Graves' disease patients than normal subjects (3.59 +/- 2.66 vs. 5.97 +/- 1.56, p < .01). The ratios also had a significant (p < .05) inverse correlation with serum gastrin concentrations in T3-predominant Graves' disease patients. The results suggest that autoimmune gastritis is associated with Graves' disease, particularly in patients with potent thyroid-autoimmunity.