LONGTERM EFFECTS OF CHRONIC HYPERGASTRINEMIA ON GASTRIC MUCOSAL ENDOCRINE CELLS

慢性高胃泌素血症引起肠色素样细胞（ECL细胞）增殖，可发展为类癌肿瘤，其中一些是恶性的。随着胃食管反流病（GERD）、H-+- k -+ atp酶抑制剂（奥美拉唑等）等常见疾病的慢性使用增加，H-+- k -+ atp酶抑制剂是强效抑酸剂，可导致bbb80 %的患者出现高胃泌素血症，人们越来越关注慢性高胃泌素血症对ECL细胞的长期胃影响。目前，在人类中，尚不清楚ECL细胞在高胃泌素血症时发生变化的时间进程、长期治疗时的严重程度、导致类癌发展的因素或识别类胃癌的最佳手段。佐林格-埃里森综合征（Zollinger-Ellison syndrome， ZES）患者终身高胃泌素血症，因为大多数患者没有治愈，因此是研究这些胃效应的良好模型。此外，25%的ZES患者有man -1，这使他们容易发展为类胃癌，因此加速了这些肿瘤的发展。为了解决慢性高胃泌素血症引起的胃ECL改变的频率和严重程度，类癌肿瘤的频率，检测它们的最佳方法和确定影响因素，意大利制药大学病理学系C. Bordi教授和意大利罗马La Sapienza的G. Delle Fave教授合作开展了一项前瞻性研究。本研究对一大批ZES患者在胃的8个固定区域定期进行系统的胃活检。此外，正在对慢性萎缩性胃炎患者进行类似的研究，慢性萎缩性胃炎也会导致慢性高胃泌素血症，用于比较的正常患者和men1患者没有ZES。所有活检都要分析ECL细胞的变化、炎症程度、形态变化和其他可能与ECL变化程度平行或有助于其增殖的蛋白质的变化，如α - HCG的表达。所有高危患者均行胃内镜超声检查（EUS）以定位类癌肿瘤。本研究将比较活检、内镜和EUS评估晚期ECL改变的能力以及类胃癌肿瘤的位置和范围。截至1999年9月，188例患者被纳入本研究。本研究应明确ECL改变的时间过程和程度，并确定慢性高胃泌素血症患者随访检测类癌肿瘤和评估其程度的最佳方法。目前正在分析活检部位对活检结果的总体影响，以及H+-K+ atp酶抑制剂患者的囊性变化（息肉形成的前体）的发展，以及没有man -1的ZES患者的结果。-高胃泌素血症，佐林格-埃里森综合征，类胃癌，ECL细胞增生，MEN1

Chronic hypergastrinemia causes proliferation of enterochromaffin-like cells (ECL cells) which can process to the development of carcinoid tumors, some of which are malignant. With their increased chronic use for common conditions such as gastroesophageal reflux disease (GERD), H-+-K-+ ATPase inhibitors (omeprazole, etc.), which are potent acid suppressants and can cause hypergastrinemia in >80% of patients, there is increased concern over the longterm gastric effects on ECL cells of chronic hypergastrinemia. Currently, it is unclear in humans, the time course of changes with hypergastrinemia in ECL cells, their severity with prolonged treatment, factors that contribute to carcinoid development or the best means to identify gastric carcinoids. Patients with Zollinger-Ellison syndrome (ZES) have life-long hypergastrinemia because most are not cured and therefore are excellent models to study these gastric effects. Furthermore, 25% of patients with ZES have MEN-1 which predisposes them to the development of gastric carcinoids and hence have accelerated development of these tumors. To address the frequency and severity of gastric ECL changes that occur with chronic hypergastrinemia, the frequency of carcinoid tumors, the best methods to detect them and the identification of contributing factors, a prospective study has been started in collaboration with Prof. C. Bordi, Dept. of Pathology, Univ. of Pharma, Italy and Prof. G. Delle Fave, La Sapienza, Rome, Italy. This study involves systematic gastric biopsies at regular intervals from 8 fixed areas in the stomach on a large cohort of patients with ZES. Furthermore, similar studies are being performed on patients with chronic atrophic gastritis, which also results in chronic hypergastrinemia, normals for comparison and patients with MEN-1 without ZES. All biopsies are analyzed for changes in the ECL cells, the degree of inflammation, morphologic changes and changes in other proteins that may parallel the extent of ECL changes or contribute to their proliferations such as the expression of alpha- HCG. All high risk patients also undergo gastric endoscopic ultrasonography (EUS) to attempt to localize carcinoid tumors. Comparison of the ability of biopsy, endoscopy and EUS to assess advanced ECL changes and the location and extent of gastric carcinoid tumors will be possible from this study. As of September 1999, 188 patients have been entered into this study. This study should allow definition of the time course and extent of ECL change as well as the definition of the best methods to follow patients with chronic hypergastrinemia to detect carcinoid tumors and assess their extent. An analysis of the overall results of the effect of biopsy site on the biopsy results, the development of cystic changes which are the precursors of polyp formation in patients on H+-K+ ATPase inhibitors and the results in patients with ZES without MEN-1 is now in progress. - hypergastrinemia, Zollinger-Ellison syndrome, gastric carcinoid, ECL cell hyperplasia, MEN1