Treatment of ECL cell carcinoids with octreotide LAR

BACKGROUND: Patients with chronic atrophic gastritis (CAG) and hypergastrinaemia are at risk of developing hyperplasia of the enterochromaffin-like (ECL) cells and ECL-cell-derived tumours. The effect of the somatostatin analogue octreotide on ECL cell carcinoids is examined. METHODS: Five patients with hypergastrinaemia and ECL cell carcinoids were enrolled in a 1-year study of octreotide LAR (long-acting release) 20 mg given at monthly intervals. Biopsies from tumours and from flat oxyntic mucosa were done at the start and 3, 6 and 12 months thereafter. Sections were stained with haematoxylin-erythrosin, immunostained with chromogranin A (CgA) and doublestained with CgA and Ki-67. Serum gastrin and CgA were measured. RESULTS: The number of visible tumours was reduced by more than 50 %. Sections from both tumours and flat mucosa showed a reduced number of CgA immunoreactive cells. Mean serum gastrin decreased from 421 to 186 pM (normal <40 pM); P > 0.05, and serum CgA from 73 to 25 ng/ml (normal < 30 ng/ml); P < 0.001. CONCLUSIONS: During treatment the patients were still markedly hypergastrinaemic, whereas the serum CgA showed normalization. A diminished tumour load and reduced ECL cell density were found, indicating an antiproliferative effect of octreotide directly on the ECL cells.     

Treatment of ECL cell carcinoids with octreotide LAR

Background: Patients with chronic atrophic gastritis (CAG) and hypergastrinaemia are at risk of developing hyperplasia of the enterochromaffin‐like (ECL) cells and ECL‐cell‐derived tumours. The effect of the somatostatin analogue octreotide on ECL cell carcinoids is examined. Methods: Five patients with hypergastrinaemia and ECL cell carcinoids were enrolled in a 1‐year study of octreotide LAR (long‐acting release) 20?mg given at monthly intervals. Biopsies from tumours and from flat oxyntic mucosa were done at the start and 3, 6 and 12 months thereafter. Sections were stained with haematoxylin‐erythrosin, immunostained with chromogranin A (CgA) and doublestained with CgA and Ki‐67. Serum gastrin and CgA were measured. Results: The number of visible tumours was reduced by more than 50 %. Sections from both tumours and flat mucosa showed a reduced number of CgA immunoreactive cells. Mean serum gastrin decreased from 421 to 186?pM (normal <40?pM); P?>?0.05, and serum CgA from 73 to 25?ng/ml (normal <30?ng/ml); P?Conclusions: During treatment the patients were still markedly hypergastrinaemic, whereas the serum CgA showed normalization. A diminished tumour load and reduced ECL cell density were found, indicating an antiproliferative effect of octreotide directly on the ECL cells.     

Octreotide inhibits the enterochromaffin-like cell but not peroxisome proliferator-induced hypergastrinemia

The peroxisome proliferator ciprofibrate induces hypergastrinemia and as a consequence, enterochromaffin-like (ECL) cell hyperplasia. The mechanism for the gastrin cell stimulation is unknown. The somatostatin analog octreotide LAR (long-acting release) was used to see if the stimulating effects of ciprofibrate could be attenuated. Female Fischer rats were dosed with ciprofibrate (50 mg/kg body weight per day) alone or combined with octreotide LAR (10 mg/30 days) for 60 days. Plasma gastrin and histamine, gastric endocrine cell densities and mRNA abundances were measured. Ciprofibrate increased gastrin mRNA abundance (P<0.05), gastrin cell number (P<0. 001) and cell area (P<0.01), and induced hypergastrinemia (P<0.001). These rats had profound ECL cell hyperplasia, confirmed by an increase in chromogranin A (CgA) and histidine decarboxylase (HDC) mRNA, density of neuroendocrine and ECL cells and plasma histamine levels (all P<0.001). Octreotide LAR did not affect ciprofibrate stimulation of gastrin cells, but all parameters of ECL cell hyperplasia were reduced (P<0.001). Octreotide LAR also significantly inhibited basal ECL cell function and growth. Ciprofibrate stimulates gastrin cell activity by a mechanism unaffected by octreotide, but octreotide does inhibit basal and gastrin-stimulated ECL cell function and growth.     

Spontaneous enterochromaffin-like cell carcinomas in cotton rats (Sigmodon hispidus) are prevented by a somatostatin analogue

Among inbred female cotton rats (Sigmodon hispidus) 25-50% of the animals develop spontaneous gastric carcinomas; the corresponding figure for male cotton rats is approximately 1%. Animals with carcinomas have hypergastrinaemia and gastric hypo-anacidity and the tumours are derived from enterochromaffin-like (ECL) cells. The mechanism behind the hypo-anacidity is unknown. Carcinomas are found in all female cotton rats with hypergastrinaemia lasting more than 4 months and this represents an excellent animal model for studying gastric carcinogenesis. In this study, the somatostatin analogue octreotide was given to female cotton rats to prevent carcinoma development caused by hypergastrinaemia. Twelve female cotton rats were given monthly injections of long-acting octreotide (5 mg i.m.) for 6 months. A control group of 20 animals was not given injections. Of the 20 control animals, 13 developed hypergastrinaemia and histologically invasive carcinomas or dysplasia. Of the 12 animals in the octreotide group, five developed hypergastrinaemia. None of these five animals developed histological cancer (P<0.05), whereas three had dysplasia. However, octreotide did not affect plasma gastrin concentration or antral gastrin mRNA abundance significantly. Dysplasia of the oxyntic mucosa in hypergastrinaemic animals was accompanied by a marked increase in chromogranin A-immunoreactive cells and cells positive for Sevier-Munger staining. The malignant tissue also contained groups of cells with Sevier-Munger staining. In conclusion, octreotide prevented ECL cell carcinomas in hypergastrinaemic cotton rats without lowering the gastrin concentration.     

Estimation of efficacy of the octreotide LAR administration in the patients with somatotropinoma

Acromegaly is caused by excessive secretion of growth hormone by a hypophyseal adenoma type of somatotropinoma. IGF-I is formed in the liver and mediates most biological actions of GH. Treatment of adenomas, which secrete GH, involves pharmacotherapy followed by surgery. Modern pharmacotherapy leaning is based on somatostatin analogues (factor restrictive secretion GH): octreotide, octreotide LAR and lanreotide. The aim of our study was estimation of efficiency of octreotide LAR in the patients with somatotropinoma prepared to neurosurgery intervention. We examined 16 patients (10 of women and 6 men) with the features of active acromegaly. In all cases the increased concentration of HGH and IGF-I were observed. The presence of pituitary adenoma in all patients was confirmed by MRI. The patients were treated with octreotide LAR monthly in dose 20 mg and 30 mg respectively. Before and after application of somatostatin analogues the concentration HGH, IGF-I, PRL in serum were marked. The concentration of GH before octreotide LAR therapy in all patients increased remarkable and ranged from 15.6 to 78.6 ng/ml, mean: 31.20 +/- 16.84 (norm: 0-10 ng/ml), also, in all cases the serum IGF-I level was increased and ranged from 451 to 1107.6 ng/ml, mean: 801.75 +/- 207.82 (norm: 100-400 ng/ml). The prolactin concentration ranged from 7.4 to 49.9 ng/ml, mean: 22.8 +/- 13.7 (norm: 2-20 ng/ml) and in 8 (50%) cases the increased of PRL concentration in serum was observed. After the administration of octreotide LAR the level of: GH [mean: 12.99 +/- 17.16 ng/ml (p < 0.001)], of IGF-I [mean 422.8 +/- 229 ng ml (p < 0.01)] statistical important decreased and prolactin in 8 with increased concentration [mean: 12.45 +/- 5.57 (p < 0.01)] were observed. Long acting somatostatin analogues--octreotide LAR is particular efficient in lowering of growth hormone and IGF-I in patients with somatotropinoma and shows efficiency in normalization of increased prolactin concentration. Because of extreme effectiveness of octreotide LAR, it should be used the routine treatment at the patients suffering from active acromegaly and preparing to neurosurgical treatment.     

Antrectomy does not accelerate reversal of omeprazole-induced trophic effects in the rat stomach.

The oxyntic mucosa in the rat stomach is under the influence of circulating gastrin. The histamine-producing enterochromaffin-like (ECL) cells constitute the major endocrine cell population in the oxyntic mucosa. They are notably sensitive to changes in the serum gastrin concentration and respond to long-term hypergastrinemia with hyperplasia, whereas hypogastrinemia induces hypoplasia. In the present study long-term, sustained hypergastrinemia was induced by daily treatment with a high dose of the proton pump inhibitor omeprazole. After 10 weeks omeprazole-treated and control rats were antrectomized, resulting in prompt hypogastrinemia. Antrectomy was followed by a rapid reduction of the thickness of the oxyntic mucosa and a somewhat slower reduction of the ECL cell number in both omeprazole-treated and control rats. The percentage decrease in the ECL cell number with time was similar in both groups; after 2-3 weeks the ECL cell number was half of that before antrectomy in both groups. Interestingly, however, 12 weeks after antrectomy the ECL cell number in the omeprazole-pretreated rats remained elevated compared with untreated rats. The histamine concentration of the oxyntic mucosa was markedly lowered within a week after antrectomy in both omeprazole-treated and control rats. Although antrectomy induces hypogastrinemia and although atrophy develops rapidly in the oxyntic mucosa, the omeprazole-induced ECL cell hyperplasia was not completely reversed by antrectomy during the 12 weeks of examination.     

Antrectomy Does Not Accelerate Reversal of Omeprazole-Induced Trophic Effects in the Rat Stomach

The oxyntic mucosa in the rat stomach is under the influence of circulating gastrin. The histamine-producing enterochromaffin-like (ECL) cells constitute the major endocrine cell population in the oxyntic mucosa. They are notably sensitive to changes in the serum gastrin concentration and respond to long-term hypergastrinemia with hyperplasia, whereas hypogastrinemia induces hypoplasia. In the present study long-term, sustained hypergastrinemia was induced by daily treatment with a high dose of the proton pump inhibitor omeprazole. After 10 weeks omeprazoie-treated and control rats were antrectomized, resulting in prompt hypogastrinemia. Antrectomy was followed by a rapid reduction of the thickness of the oxyntic mucosa and a somewhat slower reduction of the ECL cell number in both omeprazoie-treated and control rats. The percentage decrease in the ECL cell number with time was similar in both groups; after 2-3 weeks the ECL cell number was half of that before antrectomy in both groups. Interestingly, however, 12 weeks after antrectomy the ECL cell number in the omeprazole-pretreated rats remained elevated compared with untreated rats. The histamine concentration of the oxyntic mucosa was markedly lowered within a week after antrectomy in both omeprazoie-treated and control rats. Although antrectomy induces hypogastrinemia and although atrophy develops rapidly in the oxyntic mucosa, the omeprazole-induced ECL cell hyperplasia was not completely reversed by antrectomy during the 12 weeks of examination.     

Exocrine pancreatic insufficiency: accuracy and clinical value of the uniformly labelled 13C-Hiolein breath test.

BACKGROUND/AIMS--To evaluate the response of endocrine cells of the gastric oxyntic mucosa in hypergastrinaemic patients to either antrectomy or treatment with the somatostatin analogue octreotide. PATIENTS--(a) Two patients with enterochromaffin-like (ECL) cell carcinoid and chronic atrophic gastritis, treated with antrectomy; (b) four patients with Zollinger-Ellison syndrome, treated with octreotide. METHODS--Oxyntic endocrine cells were examined by ultrastructural morphometry on full thickness biopsy specimens taken: (a) before and four months after antrectomy, (b) before and after three months' treatment with octreotide 200 micrograms daily. RESULTS--Both treatments induced prompt, significant reduction of gastrinaemia and a significant decrease of the volume density of the whole endocrine cell mass and of the cross sectional area of all nucleated endocrine cell profiles (antrectomy: -38%, p < 0.04 and -31%, p < 0.04, respectively; octreotide: -59%, < 0.007 and -26%, < 0.04, respectively). Assessment of the relative proportion of individual endocrine cell types showed a different response to antrectomy or octreotide. After antrectomy, in fact, only the volume fraction of ECL cells was significantly reduced, from 56.5% to 22.5% (-60%, p < 0.04). After octreotide treatment, in contrast, the proportion of all endocrine cell types remained remarkably constant, showing that all cell types took part in the observed overall decrease. CONCLUSIONS--Postantrectomy reduction of oxyntic endocrine cells mostly reflects the withdrawal of the specific trophic stimulus of hypergastrinaemia on ECL cells. In contrast, the inhibitory response to octreotide seems to be exerted on virtually all types of oxyntic endocrine cells, probably reflecting a universal occurrence of somatostatin receptors.     

Clinical experience with Sandostatin LAR in patients with acromegaly.

Patients with acromegaly, who are not cured after transsphenoidal adenomectomy, may be treated with external irradiation and/or octreotide injections. Recently, a long-acting formulation of octreotide (Sandostatin LAR has become available in clinical practice. We assessed the effects of treatment with this long-acting octreotide in 18 consecutive patients with acromegaly treated in our center, who had persistent signs and symptoms of acromegaly despite transsphenoidal surgery with (n=7) or without irradiation (n=11). Twelve had already been treated with regular Sandostatin for a period of 0.5-8 years in dosages of 3 x 50 to 3 x 300 mcg s.c. (median daily dose 300 mcg). All patients started with i.m. injections of 20 mg Sandostatin LAR every 4 weeks. In the patients who started treatment with octreotide for the first time, mean serum IGF-1 levels (measured by IRMA, Nichols Diagnostics) decreased from 634+/-229 to 255+/-88 ng/ml after 3 months, 271+/-81 ng/ml after 1 year and 263+/-97 ng/ml after 2 years (all P<0.05), while random GH levels (DELFIA, Wallac) decreased from 6.6 (range 3.1-67.0) to 2.1 (0.5-3.1) mU/l after 2 years (P<0.05). In the 12 patients who had already been treated with octreotide, mean IGF-1 also fell, from 367+/-193 to 331+/-195 ng/ml (P=0.023) after 3 months, to 342+/-191 ng/ml after 1 year and 277+/-169 ng/ml (P=0.002) after 2 years, while random GH levels decreased from 4.5 (1.1-46) mU/l at baseline to 2.1 (0.4-23.0) after 2 years (P=0.003). Therefore, the average decrease of IGF-1 was 10% after 3 months and 25% after 2 years. One patient had a decrease of less than 5% (but her IGF-1 was normal, 193 ng/ml), and one patient showed no response to both regular and long-acting Sandostatin (ave. IGF-1, 755 ng/ml). No specific side-effects occurred. One patient chose to return to t.i.d. injection of regular octreotide because of slight worsening of her complaints of headache despite normal IGF-1 levels. All other patients favoured continuation of the monthly injections. In six patients, the dose had to be increased to 30-40 mg monthly because the IGF-1 levels still remained elevated. Sandostatin LAR may be considered a great improvement for the treatment of patients with (symptomatic) acromegaly.     

Marked increase in gastric acid secretory capacity after omeprazole treatment.

BACKGROUND: In contrast with the histamine2 (H2) blockers, proton pump inhibitors have not been shown to give rebound hypersecretion of acid. Taking into consideration the hyperplasia of the enterochromaffin-like (ECL) cell provoked by hypergastrinaemia secondary to profound acid inhibition and the central role of histamine from ECL cells in the regulation of acid secretion, the lack of any rebound acid hypersecretion after treatment with proton pump inhibitors has been questioned. AIMS: To reassess the effect of treatment with omeprazole on post-treatment acid secretion. METHODS AND PATIENTS: Basal and pentagastrin stimulated acid secretion were determined in nine patients with reflux oesophagitis before and 14 days after termination of a 90 day treatment period with the proton pump inhibitor omeprazole (40 mg daily). Basal gastrin release were determined before and during omeprazole treatment. Furthermore, biopsy samples from the oxyntic mucosa were taken before and at the end of the treatment period for chemical (histamine and chromogranin A (CgA)) evaluation of the ECL cell mass. RESULTS: A substantial increase in meal stimulated gastrin release during omeprazole treatment resulted in an increased ECL cell mass. Furthermore, CgA in serum increased during omeprazole treatment suggesting that serum CgA may be used as a test to evaluate ECL cell hyperplasia. A significant increase in basal and a marked (50%) and significant increase in pentagastrin stimulated acid secretion were found after treatment with omeprazole. CONCLUSIONS: Increased acid secretion after a conventional treatment period with a proton pump inhibitor is probably due to ECL cell hyperplasia and may have negative consequences for acid related diseases.     

The CCK-2 Receptor is Located on the ECL Cell,But Not on the Parietal Cell

Background: The interrelationship between histamine and gastrin in the physiological regulation of gastric acid secretion is still a matter of dispute. CCK-2 receptors are located on enterochromaffin-like (ECL) cells in corpus mucosa and gastrin stimulates acid production by releasing histamine from the ECL cells, which in turn stimulates the parietal cells. Whether parietal cells also possess gastrin receptors of physiological significance is unclear. The aim of the present study was to localize the CCK-2 receptor cellularly and concomitantly demonstrate a gastrin receptor response (histamine release). Methods: Fluorescein labelled cholecystokinin-8 (Fluo-CCK-8) was added to the arterial infusion to totally isolated, vascularly perfused rat stomachs to a final concentration of 130 pmol L -1 for 1 min, either alone or along with 520 nmol -1 CCK-8 after 10-min pre-perfusion with CCK-8. Immediately after the FluoCCK-8 had reached the oxyntic mucosa, biopsies were taken and the binding sites were localized by double immunohistochemistry combined with the tyramide signal amplification (TSA) technique. Venous histamine was measured before and during stimulation. Results: Fluo-CCK-8 (130 pM) evoked histamine release, and binding sites were found in the basal part of corpus mucosa, co-localized with histidine decarbocylase (HDC) immunoreactive ECL cells. No binding of Fluo-CCK was found in the midglandular region of corpus, dominated by parietal cells. Binding of Fluo-CCK-8 was abolished by concomitant perfusion with excess CCK-8. Conclusion: Fluo-CCK-8 given to isolated rat stomachs in a physiological concentration binds to CCK-2 receptors on ECL cells and causes histamine release, whereas no binding of Fluo-CCK-8 to parietal cells was found.     

The CCK-2 receptor is located on the ECL cell, but not on the parietal cell.

BACKGROUND: The interrelationship between histamine and gastrin in the physiological regulation of gastric acid secretion is still a matter of dispute. CCK-2 receptors are located on enterochromaffin-like (ECL) cells in corpus mucosa and gastrin stimulates acid production by releasing histamine from the ECL cells, which in turn stimulates the parietal cells. Whether parietal cells also possess gastrin receptors of physiological significance is unclear. The aim of the present study was to localize the CCK-2 receptor cellularly and concomitantly demonstrate a gastrin receptor response (histamine release). METHODS: Fluorescein labelled cholecystokinin-8 (Fluo-CCK-8) was added to the arterial infusion to totally isolated, vascularly perfused rat stomachs to a final concentration of 130 pmol L(-1) for 1 min, either alone or along with 520 nmol(-1) CCK-8 after 10-min pre-perfusion with CCK-8. Immediately after the Fluo-CCK-8 had reached the oxyntic mucosa, biopsies were taken and the binding sites were localized by double immunohistochemistry combined with the tyramide signal amplification (TSA) technique. Venous histamine was measured before and during stimulation. RESULTS: Fluo-CCK-8 (130 pM) evoked histamine release, and binding sites were found in the basal part of corpus mucosa, co-localized with histidine decarbocylase (HDC) immunoreactive ECL cells. No binding of Fluo-CCK was found in the mid-glandular region of corpus, dominated by parietal cells. Binding of Fluo-CCK-8 was abolished by concomitant perfusion with excess CCK-8. CONCLUSION: Fluo-CCK-8 given to isolated rat stomachs in a physiological concentration binds to CCK-2 receptors on ECL cells and causes histamine release, whereas no binding of Fluo-CCK-8 to parietal cells was found.     

Reversibility of the cell kinetic changes induced by omeprazole in the rat oxyntic mucosa. An autoradiographic study using tritiated thymidine.

Both oxyntic mucosal progenitor cells and enterochromaffin-like (ECL) cells are under the trophic control of gastrin. We studied the effect of discontinuing omeprazole-induced hypergastrinemia on cell proliferation and ECL cell function in the rat oxyntic mucosa. All rats had hypergastrinemia after 16 days' omeprazole administration, and the proliferation rate of both progenitor and ECL cells was increased, whereas it was decreased 5 days after withdrawal of omeprazole. Circulating gastrin had normalized by then. The proliferative activity of the progenitor cells returned to normal within 10 days, whereas that of the ECL cells remained suppressed for at least 20 days. The histidine decarboxylase activity of the ECL cells changed in parallel with their proliferative activity. These data suggest either a down-regulation of membrane receptors or the involvement of still unknown inhibitors of mitotic activity and ECL cell function in the oxyntic mucosa.     

Glycoprotein hormone alpha subunit in endocrine cells of human oxyntic mucosa. Studies on its relation to neuroendocrine tumors.

Expression of the alpha-subunit of glycoprotein hormones is an acquired feature of the endocrine cells of the oxyntic mucosa in patients with sustained serum levels of gastrin, and may be related to the hyperplasia-carcinoid sequence occurring in these patients. In the present study we have investigated the intragastric cellular localization and the circulating levels of alpha-subunit in a patient with Zollinger-Ellison syndrome. In this patient we have found that: 1) Endocrine cells accounted for 2.29% +/- 1.44% of the total oxyntic mucosal volume (normal value: 0.9% +/- 0.4%), with the ECL cells representing 63.22% +/- 10.9% of the total endocrine cell volume (normal value: 29.8 +/- 8.8%). 2) Cells immunoreactive for the alpha-subunit were found to correspond ultrastructurally to a subpopulation of enterochromaffin-like cells, indistinguishable from similar cells devoid of significant immuno-electron microscopic labeling. 3) Immunoreactive cells included a portion of oxyntic endocrine cells with punctate granules, a feature previously observed only in carcinoid tumors of the oxyntic mucosa. 4) In consecutive sections of freeze-dried vapor-fixed biopsies a fraction of alpha-subunit storing cells was found to co-express histamine. 5) The serum alpha-subunit levels were abnormally elevated and paralleled those of gastrin in a secretin-stimulation test. Analysis of similar curves in two other patients with Zollinger-Ellison syndrome, and five patients with hypergastrinemic atrophic gastritis, all presenting alpha-subunit containing oxyntic endocrine cells, showed significant alpha-subunit elevations only in the patients with ulcerogenic syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)     

Partial gastric corpectomy results in hypergastrinemia and development of gastric enterochromaffinlike-cell carcinoids in the rat

Studies in the rat have shown that partial gastric corpectomy, in which about 75% of the acid-producing oxyntic mucosa was removed, leads to markedly reduced acid secretion and a feedback increase in the plasma gastrin levels. Ten weeks after operation, the gastric enterochromaffin (ECL)-like cell density in the remaining part of the oxyntic mucosa had increased significantly. In the present study, the effects on the gastric ECL cells of lifelong persistent hypergastrinemia induced by partial (75%) corpectomy have been investigated. Seventy-five partially corpectomized rats and 40 control rats were investigated for plasma gastrin and oxyntic mucosal changes in a 124-week study. The partially corpectomized rats showed increased plasma gastrin levels after the operation; the mean increase compared with the controls was almost 10-fold during the entire study. The remaining oxyntic mucosa of the partially corpectomized rats differed from that of control rats in two respects, showing first general hypertrophy and second a marked hyperplasia of argyrophil ECL cells. The degree and incidence of these changes increased towards the end of the study, i.e., in the aging rats. An age-related increase in ECL-cell density occurred spontaneously also in the control rats but to a lesser extent than in the partially corpectomized group. ECL-cell carcinoids were found in the oxyntic mucosa of 26 of the 75 partially corpectomized rats. The first carcinoid was found 78 weeks after the beginning of the study. Six rats with carcinoids (23%) were found before week 104 (2 years) and the remainder, 20 (77%), were discovered later. No carcinoid tumor was found in the control rats. It is concluded that lifelong hypergastrinemia induced by partial corpectomy leads to the development of ECL-cell carcinoids in the oxyntic mucosa of some rats towards the end of their life span. This observation strongly supports the hypothesis that the gastric ECL-cell carcinoids found in rats treated with antisecretory drugs are caused by long-standing hypergastrinemia developing secondary to inhibition of gastric acid secretion.     

Clinical significance of elevated serum chromogranin A levels

BACKGROUND: Chromogranin A (CgA) has been shown to be a useful marker in the diagnosis of neuroendocrine (NE) tumours. The clinical significance of CgA has been studied mostly in patients with known NE tumours. The diagnosis was evaluated in 153 consecutive patients in whom CgA was measured in a given time interval. METHODS: CgA in serum was measured by radioimmunoassay. Immunohistochemistry with an antibody against CgA was performed in tumours from patients with adenocarcinoma and elevated CgA levels using a conventional method and the more sensitive tyramide signal amplification (TSA) technique. RESULTS: Elevated serum CgA levels were found in 44 patients; 19 had NE tumours and 6 had tumours classified as adenocarcinomas. With the TSA technique, a high proportion of CgA-positive cells were disclosed in five of the adenocarcinoma patients. Patients with atrophic gastritis (no. 2) and patients treated with inhibitors of gastric acid secretion (no. 6) also had elevated levels of CgA. A modest increase in CgA levels was observed in 2 patients with renal impairment, and in 9 patients without any obvious cause. CONCLUSION: The current study confirms that serum CgA is a sensitive marker for the detection of NE neoplasia. Elevated levels found in patients with adenocarcinoma may indicate NE differentiation in the tumour. CgA is a useful tool in the monitoring of enterochromaffin-like (ECL) hyperplasia secondary to treatment with acid secretion inhibitors or atrophic gastritis.     

Effects of 5 years of treatment with rabeprazole or omeprazole on the gastric mucosa

BACKGROUND: Prolonged gastric acid suppression leads to hypergastrinaemia, which promotes hyperplasia of the enterochromaffin-like (ECL) cells of the oxyntic mucosa. The objective was to determine the effects of 5 years of treatment with rabeprazole or omeprazole on the gastric mucosa. METHODS: Two hundred and forty-three patients received rabeprazole (20 mg or 10 mg) or omeprazole (20 mg) once daily for up to 5 years, for gastro-oesophageal reflux disease and 51% completed the whole 5 year period. Gastric biopsy specimens were taken and examined for gastritis, Helicobacter pylori infection, and ECL cell status. FINDINGS: H. pylori infection in the gastric corpus was more common than in the antrum, and remained constant, whereas antral H. pylori infection became less common as the study progressed. H. pylori infection was a highly significant predictor of higher gastritis scores, which were similar among the three treatment groups. ECL cell hyperplasia occurred in a minority of patients, and was associated with serum gastrin concentrations. No ECL cell dysplasia or tumours were observed. There were no significant differences among the treatment groups in gastritis or ECL cell hyperplasia grades. INTERPRETATION: This study has confirmed the link between ECL cell hyperplasia and elevated serum gastrin concentrations, but has found no evidence that this progresses to high grades of hyperplasia during 5 years of treatment with rabeprazole or omeprazole.     

Control of gastric acid secretion in somatostatin receptor 2 deficient mice: shift from endocrine/paracrine to neurocrine pathways

The gastrin-enterochromaffin-like (ECL) cell-parietal cell axis is known to play an important role in the regulation of gastric acid secretion. Somatostatin, acting on somatostatin receptor type 2 (SSTR(2)), interferes with this axis by suppressing the activity of the gastrin cells, ECL cells, and parietal cells. Surprisingly, however, freely fed SSTR(2) knockout mice seem to display normal circulating gastrin concentration and unchanged acid output. In the present study, we compared the control of acid secretion in these mutant mice with that in wild-type mice. In SSTR(2) knockout mice, the number of gastrin cells was unchanged; whereas the numbers of somatostatin cells were reduced in the antrum (-55%) and increased in the oxyntic mucosa (35%). The ECL cells displayed a reduced expression of histidine decarboxylase and vesicle monoamine transport type 2 (determined by immunohistochemistry), and an impaired transformation of the granules to secretory vesicles (determined by electron microscopic analysis), suggesting low activity of the ECL cells. These changes were accompanied by an increased expression of galanin receptor type 1 in the oxyntic mucosa. The parietal cells were found to respond to pentagastrin or to vagal stimulation (evoked by pylorus ligation) with increased acid production. In conclusion, the inhibitory galanin-galanin receptor type 1 pathway is up-regulated in the ECL cells, and the direct stimulatory action of gastrin and vagal excitation is enhanced on the parietal cells in SSTR(2) knockout mice. We suggest that there is a remodeling of the neuroendocrine mechanisms that regulate acid secretion in these mutant mice.     

Clinical significance of elevated serum chromogranin A levels

Background: Chromogranin A (CgA) has been shown to be a useful marker in the diagnosis of neuroendocrine (NE) tumours. The clinical significance of CgA has been studied mostly in patients with known NE tumours. The diagnosis was evaluated in 153 consecutive patients in whom CgA was measured in a given time interval. Methods: CgA in serum was measured by radioimmunoassay. Immunohistochemistry with an antibody against CgA was performed in tumours from patients with adenocarcinoma and elevated CgA levels using a conventional method and the more sensitive tyramide signal amplification (TSA) technique. Results: Elevated serum CgA levels were found in 44 patients; 19 had NE tumours and 6 had tumours classified as adenocarcinomas. With the TSA technique, a high proportion of CgA‐positive cells were disclosed in five of the adenocarcinoma patients. Patients with atrophic gastritis (no. 2) and patients treated with inhibitors of gastric acid secretion (no. 6) also had elevated levels of CgA. A modest increase in CgA levels was observed in 2 patients with renal impairment, and in 9 patients without any obvious cause. Conclusion: The current study confirms that serum CgA is a sensitive marker for the detection of NE neoplasia. Elevated levels found in patients with adenocarcinoma may indicate NE differentiation in the tumour. CgA is a useful tool in the monitoring of enterochromaffin‐like (ECL) hyperplasia secondary to treatment with acid secretion inhibitors or atrophic gastritis.