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Ito T, Ramos-Alvarez I, Jensen RT. Successful Lifetime/Long-Term Medical Treatment of Acid Hypersecretion in Zollinger-Ellison Syndrome (ZES): Myth or Fact? Insights from an Analysis of Results of NIH Long-Term Prospective Studies of ZES. Cancers (Basel) 2023; 15:1377. [PMID: 36900170 PMCID: PMC10000208 DOI: 10.3390/cancers15051377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/09/2023] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Analysis of the efficacy/pharmacology of long-term/lifetime medical treatment of acid hypersecretion in a large cohort of ZES patients in a prospective study. This study includes the results from all 303 patients with established ZES who were prospectively followed and received acid antisecretory treatment with either H2Rs or PPIs, with antisecretory doses individually titrated by the results of regular gastric acid testing. The study includes patients treated for short-term periods (<5 yrs), patients treated long-term (>5 yrs), and patients with lifetime treatment (30%) followed for up to 48 years (mean 14 yrs). Long-term/lifelong acid antisecretory treatment with H2Rs/PPIs can be successfully carried out in all patients with both uncomplicated and complicated ZES (i.e., with MEN1/ZES, previous Billroth 2, severe GERD). This is only possible if drug doses are individually set by assessing acid secretory control to establish proven criteria, with regular reassessments and readjustments. Frequent dose changes both upward and downward are needed, as well as regulation of the dosing frequency, and there is a primary reliance on the use of PPIs. Prognostic factors predicting patients with PPI dose changes are identified, which need to be studied prospectively to develop a useful predictive algorithm that could be clinically useful for tailored long-term/lifetime therapy in these patients.
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Affiliation(s)
- Tetsuhide Ito
- Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital, International University of Health and Welfare, 3-6-45 Momochihama, Sawara-Ku, Fukuoka 814-0001, Japan
| | | | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA
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Manoharan J, Anlauf M, Albers MB, Denzer UW, Mintziras I, Wächter S, Di Fazio P, Bollmann C, Bartsch DK. Gastric enterochromaffin-like cell changes in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 2021; 95:439-446. [PMID: 33506527 DOI: 10.1111/cen.14430] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/08/2020] [Accepted: 01/10/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES. METHODS Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed. RESULTS Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5 mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n = 22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206 pg/ml vs. 30.5 pg/ml, p < .001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p = .302, chromogranin A: p = .464). CONCLUSION Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.
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Affiliation(s)
- Jerena Manoharan
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Martin Anlauf
- Institute of Pathology and Cytology, Wetzlar, Germany
| | - Max B Albers
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Ulrike W Denzer
- Department of Gastroenterology, Philipps University Marburg, Marburg, Germany
| | - Ioannis Mintziras
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Sabine Wächter
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Carmen Bollmann
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
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Tumor Classification Should Be Based on Biology and Not Consensus: Re-Defining Tumors Based on Biology May Accelerate Progress, An Experience of Gastric Cancer. Cancers (Basel) 2021; 13:cancers13133159. [PMID: 34202596 PMCID: PMC8269176 DOI: 10.3390/cancers13133159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/14/2021] [Accepted: 06/21/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Rational treatment of diseases including cancers depends on knowledge of their cause as well as their development. The present review is based upon more than 40 years’ work in clinical gastroenterology, gastric physiology, and pathology. The central role of hormones as well as local endocrine cells in cancer development has become apparent. Moreover, the classification of tumors should focus not only on the organ of origin but also on the cell of origin. All cells with the ability to divide may give rise to tumors. Based upon knowledge of the growth regulation of the cell of origin, prophylaxis and treatment may be tailored. Presently, there is hope for individual treatment of cancer patients based upon genetic analyses of tumors. However, with correct identification of the cell of origin, this may not be necessary. Abstract Malignant tumors are a consequence of genetic changes mainly occurring during cell division, sometimes with a congenital component. Therefore, accelerated cell divisions will necessarily predispose individuals, whether due to conditions of chronic cell destruction or hormonal overstimulation. It has been postulated that two genetic hits are necessary for the development of malignancy (Knudson). The correct view is probably that the number of genetic changes needed depends on the role the mutated genes have in proliferation and growth control. Hormones should accordingly be regarded as complete carcinogens. In this review based upon experience of gastric cancer where gastrin is central in the pathogenesis, it is argued that oxyntic atrophy—and not metaplasia as postulated by Correa—is the central precancer change in gastric mucosa. Moreover, the target cell of gastrin, the enterochromaffin-like (ECL) cell, is central in gastric carcinogenesis and most probably the cell of origin of gastric carcinomas of the diffuse type according to Lauren (a classification probable in accordance with biology). The distinction between adenocarcinomas and neuroendocrine carcinomas based upon a certain percentage of cancer cells with neuroendocrine differentiation is questioned. To make progress in the treatment of cancer, a correct classification system and knowledge of the pathogenesis are necessary.
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Towards Understanding of Gastric Cancer Based upon Physiological Role of Gastrin and ECL Cells. Cancers (Basel) 2020; 12:cancers12113477. [PMID: 33266504 PMCID: PMC7700139 DOI: 10.3390/cancers12113477] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/19/2020] [Accepted: 11/21/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Generally, we know that cancers represent genetic changes in tumour cells, but we most often do not know the causes of cancers or how they develop. Our knowledge of the regulation of gastric acid secretion is well known, with the gastric hormone gastrin maintaining gastric acidity by stimulation of the enterochromaffin-like (ECL) cell to release histamine, which subsequently augments acid secretion. Furthermore, it seems to be a general principle that stimulation of function (which, for the ECL cell, is release of histamine) in a parallel way stimulates the proliferation of the same cell. Long-term hyperstimulation of cell division predisposes to genetic changes and, thus, development of tumours. All conditions with reduced gastric acidity result in an increased risk of gastric tumours due to elevated gastrin in order to restore gastric acidity. It is probable that Helicobacter pylori infection (the most important cause of gastric cancer), as well as drugs inhibiting gastric acid secretion induce gastric cancer in the long-term, due to an elevation of gastrin caused by reduced gastric acidity. Gastric carcinomas have been shown to express ECL cell markers, further strengthening this relationship. Abstract The stomach is an ideal organ to study because the gastric juice kills most of the swallowed microbes and, thus, creates rather similar milieu among individuals. Combined with a rather easy access to gastric juice, gastric physiology was among the first areas to be studied. During the last century, a rather complete understanding of the regulation of gastric acidity was obtained, establishing the central role of gastrin and the histamine producing enterochromaffin-like (ECL) cell. Similarly, the close connection between regulation of function and proliferation became evident, and, furthermore, that chronic overstimulation of a cell with the ability to proliferate, results in tumour formation. The ECL cell has long been acknowledged to give rise to neuroendocrine tumours (NETs), but not to play any role in carcinogenesis of gastric adenocarcinomas. However, when examining human gastric adenocarcinomas with the best methods presently available (immunohistochemistry with increased sensitivity and in-situ hybridization), it became clear that many of these cancers expressed neuroendocrine markers, suggesting that some of these tumours were of neuroendocrine, and more specifically, ECL cell origin. Thus, the ECL cell and its main regulator, gastrin, are central in human gastric carcinogenesis, which make new possibilities in prevention, prophylaxis, and treatment of this cancer.
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Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol 2020; 12:791-807. [PMID: 32879660 PMCID: PMC7443843 DOI: 10.4251/wjgo.v12.i8.791] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/26/2020] [Accepted: 07/18/2020] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological, biological, and clinical characteristics that have increased in incidence and prevalence within the last few decades. They contain chromogranin A, synaptophysin and neuron-specific enolase which are necessary for making a diagnosis of neuroendocrine tumor. Ki-67 index and mitotic index correlate with cellular proliferation. Serum chromogranin A is the most commonly used biomarker to assess the bulk of disease and monitor treatment and is raised in both functioning and non-functioning neuroendocrine tumors. Most of the gastrointestinal neuroendocrine tumors are non-functional. World Health Organization updated the classification of neuroendocrine tumors in 2017 and renamed mixed adenoneuroendocrine carcinoma into mixed neuroendocrine neoplasm. Gastric neuroendocrine tumors arise from enterochromaffin like cells. They are classified into 4 types. Only type I and type II are gastrin dependent. Small intestinal neuroendocrine tumor is the most common small bowel malignancy. More than two-third of them occur in the terminal ileum within 60 cm of ileocecal valve. Patients with small intestinal neuroendrocrine tumors frequently show clinical symptoms and develop distant metastases more often than those with neuroendocrine tumors of other organs. Duodenal and jejuno-ileal neuroendocrine tumors are distinct biologically and clinically. Carcinoid syndrome generally occurs when jejuno-ileal neuroendocrine tumors metastasize to the liver. Appendiceal neuroendocrine tumors are generally detected after appendectomy. Colonic neuroendocrine tumors generally present as a large tumor with local or distant metastasis at the time of diagnosis. Rectal neuroendocrine tumors are increasingly being diagnosed since the implementation of screening colonoscopy in 2000. Gastrointestinal neuroendocrine tumors are diagnosed and staged by endoscopy with biopsy, endoscopic ultrasound, serology of biomarkers, imaging studies and functional somatostatin scans. Various treatment options are available for curative and palliative treatment of gastrointestinal neuroendocrine tumors.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Lee L, Ramos-Alvarez I, Ito T, Jensen RT. Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome. Int J Mol Sci 2019; 20:5128. [PMID: 31623145 PMCID: PMC6829234 DOI: 10.3390/ijms20205128] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/08/2019] [Accepted: 10/13/2019] [Indexed: 02/07/2023] Open
Abstract
The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA.
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
| | | | - Tetsuhide Ito
- Neuroendocrine Tumor Centra, Fukuoka Sanno Hospital, International University of Health and Welfare 3-6-45 Momochihama, Sawara-Ku, Fukuoka 814-0001, Japan.
| | - Robert T Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA.
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Dacha S, Razvi M, Massaad J, Cai Q, Wehbi M. Hypergastrinemia. Gastroenterol Rep (Oxf) 2015; 3:201-8. [PMID: 25698559 PMCID: PMC4527266 DOI: 10.1093/gastro/gov004] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/08/2015] [Indexed: 12/26/2022] Open
Abstract
Gastrin is an important hormone of the digestive system, which assists gastric acid secretion. It may be pathologically elevated in conditions such as Zollinger-Ellison syndrome, or due to common medications such as proton pump inhibitors. In this review we provide an overview of the pathophysiology and medical causes of hypergastrinemia, diagnostic testing and clinical consequences of chronic hypergastrinemia.
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Affiliation(s)
- Sunil Dacha
- Internal Medicine, Emory University, Atlanta, GA, USA
| | | | - Julia Massaad
- Internal Medicine, Emory University, Atlanta, GA, USA
| | - Qiang Cai
- Internal Medicine, Emory University, Atlanta, GA, USA
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Berna MJ, Annibale B, Marignani M, Luong TV, Corleto V, Pace A, Ito T, Liewehr D, Venzon DJ, Delle Fave G, Bordi C, Jensen RT. A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors. J Clin Endocrinol Metab 2008; 93:1582-1591. [PMID: 18270260 PMCID: PMC2386679 DOI: 10.1210/jc.2007-2279] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2007] [Accepted: 01/31/2008] [Indexed: 02/08/2023]
Abstract
CONTEXT Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. OBJECTIVES Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines. SETTING AND PATIENTS Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. INTERVENTIONS AND OUTCOME MEASURES Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features. RESULTS ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid. CONCLUSIONS Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies.
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Affiliation(s)
- Marc J Berna
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1804, USA
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Berna MJ, Jensen RT. Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases. Curr Top Med Chem 2007; 7:1211-31. [PMID: 17584143 PMCID: PMC2718729 DOI: 10.2174/156802607780960519] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
In this paper, the established and possible roles of CCK1 and CCK2 receptors in gastrointestinal (GI) and metabolic diseases are reviewed and available results from human agonist/antagonist studies are discussed. While there is evidence for the involvement of CCK1R in numerous diseases including pancreatic disorders, motility disorders, tumor growth, regulation of satiety and a number of CCK-deficient states, the role of CCK1R in these conditions is not clearly defined. There are encouraging data from several clinical studies of CCK1R antagonists in some of these conditions, but their role as therapeutic agents remains unclear. The role of CCK2R in physiological (atrophic gastritis, pernicious anemia) and pathological (Zollinger-Ellison syndrome) hypergastrinemic states, its effects on the gastric mucosa (ECL cell hyperplasia, carcinoids, parietal cell mass) and its role in acid-peptic disorders are clearly defined. Furthermore, recent studies point to a possible role for CCK2R in a number of GI malignancies. Current data from human studies of CCK2R antagonists are presented and their potential role in the treatment of these conditions reviewed. Furthermore, the role of CCK2 receptors as targets for medical imaging is discussed.
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Affiliation(s)
- Marc J. Berna
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Robert T. Jensen
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine (Baltimore) 2006; 85:295-330. [PMID: 17108778 PMCID: PMC9806863 DOI: 10.1097/01.md.0000236956.74128.76] [Citation(s) in RCA: 146] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The assessment of fasting serum gastrin (FSG) is essential for the diagnosis and management of patients with the Zollinger-Ellison syndrome (ZES). Although many studies have analyzed FSG levels in patients with gastrinoma, limited information has resulted from these studies because of their small size, different methodologies, and lack of correlations of FSG levels with clinical, laboratory, or tumor features in ZES patients. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of 309 patients with ZES and compare our results with those of 2229 ZES patients in 513 small series and case reports in the literature. In the NIH and literature ZES patients, normal FSG values were uncommon (0.3%-3%), as were very high FSG levels >100-fold normal (4.9%-9%). Two-thirds of gastrinoma patients had FSG values <10-fold normal that overlap with gastrin levels seen in more common conditions, like Helicobacter pylori infection or antral G-cell hyperplasia/hyperfunction. In these patients, FSG levels are not diagnostic of ZES, and gastrin provocative tests are needed to establish the diagnosis. Most clinical variables (multiple endocrine neoplasia type 1 status, presence or absence of the most common symptoms, prior medical treatment) are not correlated with FSG levels, while a good correlation of FSG values was found with other clinical features (prior gastric surgery, diarrhea, duration from onset to diagnosis). Increasing basal acid output, but not maximal acid output correlated closely with increasing FSG. Numerous tumoral features correlated with the magnitude of FSG in our study, including tumor location (pancreatic > duodenal), primary size (larger > smaller) and extent (liver metastases > local disease). In conclusion, this detailed analysis of FSG in a large number of patients with ZES allowed us to identify important clinical guidelines that should contribute to improved diagnosis and management of patients with ZES.
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Affiliation(s)
- Marc J Berna
- From Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Jensen RT. Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol 2006; 98:4-19. [PMID: 16433886 DOI: 10.1111/j.1742-7843.2006.pto_378.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo-/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.
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Affiliation(s)
- Robert T Jensen
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1804, USA.
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Norton JA, Melcher ML, Gibril F, Jensen RT. Gastric carcinoid tumors in multiple endocrine neoplasia-1 patients with Zollinger-Ellison syndrome can be symptomatic, demonstrate aggressive growth, and require surgical treatment. Surgery 2004; 136:1267-1274. [PMID: 15657586 DOI: 10.1016/j.surg.2004.06.057] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastric carcinoid tumors occur in 15% to 50% of patients with multiple endocrine neoplasia-1/Zollinger-Ellison syndrome (MEN-1/ZES) but are thought to be benign. We report 5 patients with MEN-1/ZES with symptomatic, aggressive gastric carcinoid tumors that required surgical procedures. METHODS This was a retrospective chart review. RESULTS Each patient had MEN-1/ZES. Each patient had innumerable gastric carcinoid tumors with symptoms. The fasting gastrin level was 47,000 pg/mL (normal, <200 pg/mL); the basal acid output was 79 mEq/hr (n = 3), and the age at surgical exploration was 47 +/- 6 years, with a duration of MEN-1 of 21 +/- 3 years and of ZES of 15 +/- 2 years. All patients had elevated 5-HIAA or serotonin levels. Somatostatin receptor scintigraphy showed increased stomach uptake in 4 patients (80%). Four patients had a total gastrectomy; 4 patients had lymph node metastases removed, and 3 patients had liver metastases resected. One patient who did not have a total gastrectomy had liver carcinoid metastases. CONCLUSIONS These results demonstrate that gastric carcinoid tumors in patients with longstanding MEN-1/ZES may be symptomatic, aggressive, and metastasize to the liver. With increased long-term medical treatment and life expectancy, these tumors will become an important determinant of survival.
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Affiliation(s)
- Jeffrey A Norton
- Department of Surgery, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5651, USA
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Gibril F, Jensen RT. Zollinger-Ellison syndrome revisited: diagnosis, biologic markers, associated inherited disorders, and acid hypersecretion. Curr Gastroenterol Rep 2004; 6:454-463. [PMID: 15527675 DOI: 10.1007/s11894-004-0067-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Despite general awareness of Zollinger-Ellison syndrome (ZES) by most physicians and more than 3000 articles written about it since 1955, the diagnosis of ZES is still delayed for a mean of 5 years. Recent studies show it is being delayed even more with the widespread use of proton pump inhibitors. A number of tumor markers, in addition to assessing serum gastrin, such as chromogranin A, neuron-specific enolase, and subunits of chorionic gonadotropin, have been proposed for use in either the diagnosis of pancreatic endocrine tumors, such as gastrinomas, or for assessment of tumor extent and growth. In this article important recent insights into the diagnosis of ZES as well as the clinical usefulness of assessing tumor markers for diagnosis and determination of disease extent and growth are discussed. Approximately 25% of ZES cases are due to multiple endocrine neoplasia type 1 (MEN1). A number of important studies in this group of patients are also reviewed. Finally, almost every patient with ZES has marked gastric acid hypersecretion, and its current treatment as well as the long-term possible side effects are reviewed briefly.
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Affiliation(s)
- Fathia Gibril
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9C-103, 10 Center Drive MSC 1804, Bethesda, MD 20892-1804, USA
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Jensen RT. Involvement of cholecystokinin/gastrin-related peptides and their receptors in clinical gastrointestinal disorders. PHARMACOLOGY & TOXICOLOGY 2002; 91:333-350. [PMID: 12688377 DOI: 10.1034/j.1600-0773.2002.910611.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In this paper the possible roles of cholecystokinin (CCK), gastrin, or gastrin-related peptides and their receptors in human gastrointestinal diseases are reviewed. For CCK/CCK(A) receptors (CCK(A)-R), the evidence for their proposed involvement in diseases caused by impaired CCK release or CCK(A)-R mutations, pancreatic disorders (acute/chronic pancreatitis), gastrointestinal motility disorders (gallbladder disease, irritable bowel syndrome), pancreatic tumor growth and satiety disorders, is briefly reviewed. The evidence that has established the involvement of gastrin/CCK(B)-R in mediating the action of hypergastrinaemic disorders, mediating hypergastrinaemic effects on the gastric mucosa (ECL hyperplasia, carcinoids, parietal cell mass), and acid-peptic diseases, is reviewed. The evidence for their possible involvement in mediating growth of gastric and pancreatic tumours and possible involvement of gastrin-related peptides in colon cancers, is reviewed briefly.
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Affiliation(s)
- Robert T Jensen
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1804, USA.
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Peghini PL, Annibale B, Azzoni C, Milione M, Corleto VD, Gibril F, Venzon DJ, Delle Fave G, Bordi C, Jensen RT. Effect of chronic hypergastrinemia on human enterochromaffin-like cells: insights from patients with sporadic gastrinomas. Gastroenterology 2002; 123:68-85. [PMID: 12105835 DOI: 10.1053/gast.2002.34231] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS The effect of chronic hypergastrinemia alone on gastric enterochromaffin-like (ECL) cells in humans is largely unknown because in the common chronic hypergastrinemic states (atrophic gastritis, chronic proton pump inhibitor use), it is not possible to separate the effect of hypergastrinemia and other factors, such as gastritis or atrophy. Studies of patients with sporadic Zollinger-Ellison syndrome (ZES) allow this separation. METHODS In 106 patients with ZES, gastric biopsies were taken, and the qualitative ECL cell pattern/grade and the alpha-subunit of human chorionic gonadotropin (alpha-hCG) expression were determined. RESULTS In patients with active disease, 99% had ECL hyperplasia and abnormal alpha-hCG staining. Fifty percent had advanced changes in both of these, with 7% having dysplasia and 0% having carcinoids. Advanced ECL cell and alpha-hCG changes were most affected by the level of hypergastrinemia. For ECL cell changes, even mild hypergastrinemia had an effect. Advanced ECL change was also affected by the duration of drug treatment, cure status, and presence of atrophic gastritis, but not by sex or previous vagotomy. The alpha-hCG expression independently predicted dysplasia. CONCLUSIONS In humans, chronic hypergastrinemia alone causes advanced ECL cell change and abnormal expression of mucosal alpha-hCG. No threshold for this effect was detected, as reported by some, and in contrast to animal studies, sex and vagal tone did not play a major role. The long-term risk of developing gastric carcinoids with chronic hypergastrinemia is low in patients with sporadic gastrinomas (at least 100 times less than in patients with multiple endocrine neoplasia type 1 with ZES) for at least 15-20 years.
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Affiliation(s)
- Paolo L Peghini
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1804, USA
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Bashir S, Gibril F, Ojeaburu JV, Asgharian B, Entsuah LK, Ferraro G, Crafa P, Bordi C, Jensen RT. Prospective study of the ability of histamine, serotonin or serum chromogranin A levels to identify gastric carcinoids in patients with gastrinomas. Aliment Pharmacol Ther 2002; 16:1367-1382. [PMID: 12144588 DOI: 10.1046/j.1365-2036.2002.01249.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Chronic hypergastrinaemia causes gastric enterochromaffin cell proliferation and carcinoid tumours. The only reliable means to diagnose enterochromaffin cell changes/carcinoids is by biopsy. AIM To assess whether serum histamine, chromogranin A or serotonin and urinary N-methylimidazoleacetic acid or 5-hydroxyindoleacetic acid correlate with advanced enterochromaffin cell changes or gastric carcinoids in patients with gastrinomas. METHODS Consecutive patients (n=145) had the above assays and endoscopy with gastric biopsies. RESULTS Lower N-methylimidazoleacetic acid and chromogranin A levels (P < 0.0001) occurred in disease-free patients. In patients with active disease, the fasting serum gastrin levels correlated (P < 0.0001) with both chromogranin A and N-methylimidazoleacetic acid levels. Chromogranin A (P=0.005), but not N-methylimidazoleacetic acid, serotonin, 5-hydroxyindoleacetic acid or histamine levels, correlated with the enterochromaffin cell index. Carcinoids, but not advanced enterochromaffin cell changes only, were associated with higher chromogranin A and N-methylimidazoleacetic acid levels. CONCLUSIONS Serum chromogranin A levels and urinary N-methylimidazoleacetic acid levels, but not serum histamine or serotonin or urinary 5-hydroxyindoleacetic acid, correlate with the presence of gastric carcinoids. However, no assay identified patients with advanced enterochromaffin cell changes only with high sensitivity/specificity. Thus, N-methylimidazoleacetic acid and chromogranin A levels are unable to identify patients with advanced changes in enterochromaffin cells and therefore neither can replace routine gastric biopsies.
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Affiliation(s)
- S Bashir
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1804, USA
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Delle Fave G, Marignani M, Corleto VD, Angeletti S, D'Ambra G, Ferraro G, D'Adda T, Azzoni C, Jensen RT, Annibale B, Bordi C. Progression of gastric enterochromaffin-like cells growth in Zollinger-Ellison syndrome and atrophic body gastritis patients. Dig Liver Dis 2002; 34:270-278. [PMID: 12038811 DOI: 10.1016/s1590-8658(02)80147-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Enterochromaffin-like cell hyperplasia of the gastric body mucosa occurs in hypergastrinaemic conditions such as atrophic body gastritis and Zollinger-Ellison syndrome. However, the time course of change or factors involved are not known. AIMS To compare the rate of change of enterochromaffin-like cell proliferation in patients with atrophic body gastritis and Zollinger-Ellison syndrome. PATIENTS From a consecutive series of atrophic body gastritis and Zollinger-Ellison syndrome patients, studied at the time of first diagnosis, 10 atrophic body gastritis (4 with pernicious anaemia) and 14 Zollinger-Ellison syndrome (4 with multiple endocrine neoplasia type 1) patients were followed-up for a median time of 48 months. METHODS At entry and during follow-up patients underwent: plasma gastrin determination, endoscopic sampling of body mucosa for qualitative assessment of enterochromaffin-like cell hyperplasia pattern and degree of glandular atrophy, qualitative and morphometric analyses of body mucosa endocrine cells. RESULTS At time of diagnosis, enterochromaffin-like cell lesions were more severe in atrophic body gastritis than in Zollinger-Ellison syndrome. During follow-up, no significant variations were observed in gastrin values, enterochromaffin-like cell patterns and grade of body mucosa atrophy in atrophic body gastritis. In contrast, gastrin levels were significantly increased [median 1200 (235-2625) vs 1947 (225-5200) pg/ml; p<0.001)] as was total volume density of enterochromaffin-like cells [median 1.60 (0.53-4.06) vs 3.18 (1.35-21.13)% of mucosal epithelial component; (p<0.005)] in Zollinger-Ellison syndrome. Micronodular hyperplasia of enterochromaffin-like cells, present in only one patient at diagnosis, was observed in 8 Zollinger-Ellison syndrome patients at follow-up. CONCLUSIONS These data suggest that the progression of enterochromaffin-like cell growth in human gastric mucosa requires an increase of and/or a prolonged exposure to severe hypergastrinaemia.
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Affiliation(s)
- G Delle Fave
- Division of Digestive and Liver Diseases, 2nd School of Medicine, University La Sapienza, Rome, Italy.
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Abstract
Gastrinoma treatment has evolved considerably in the last 20 years. In particular, the advent of effective acid-reducing pharmacologic agents has changed the primary morbidity of this disease entity from one of acid hypersecretion to one of tumor growth and spread. Thus, while symptoms can be temporized using histamine receptor antagonists, proton pump inhibitors, or somatostatin analogs, cure can be effected only by surgical means. Recent advances in operative techniques and pre- and intra-operative imaging studies, including routine duodenotomy, somatostatin-receptor scintigraphy, and intraoperative ultrasound, have allowed for identification and subsequent resection of more than 95% of gastrinoma tumors. Most experts agree that all sporadic cases of localized gastrinoma should be excised. In addition, debulking of metastatic tumor may improve symptoms and survival when cure cannot be ascertained. There is, however, some controversy as to the surgical approach for gastrinoma found in the setting of multiple endocrine neoplasia, type 1. Because of the usual multiplicity and particular indolence of these tumors, two primary strategies have emerged: aggressive approaches have been advocated in an effort to eradicate all present and potential tumor; and less aggressive, or nonoperative, approaches have been suggested because it is unclear whether intervention offers survival or disease-free benefit in this population. We advocate surgical intervention for patients with gastrinoma and multiple endocrine neoplasia, type 1 when tumors exceed 2.5 cm in size. This tumor size has been associated with a higher likelihood of hepatic metastases, which ultimately affects survival. The role of adjuvant therapies for gastrinoma remains limited.
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Affiliation(s)
- M L Li
- Department of Surgery, University of California, San Francisco, USA
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Lehy T, Roucayrol AM, Mignon M. Histomorphological characteristics of gastric mucosa in patients with Zollinger-Ellison syndrome or autoimmune gastric atrophy: role of gastrin and atrophying gastritis. Microsc Res Tech 2000; 48:327-38. [PMID: 10738314 DOI: 10.1002/(sici)1097-0029(20000315)48:6<327::aid-jemt3>3.0.co;2-l] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The role of gastrin in the pathophysiology of two diseases affecting the human stomach, the Zollinger Ellison syndrome (ZES) and the pernicious anemia (PA), is reviewed. Both diseases present chronic hypergastrinemia but from different origins. The ZES is characterized by the occurrence of ectopic endocrine gastrin-secreting tumors and PA by a fundic atrophic gastritis leading to complete atrophy of fundus and resulting in achlorhydria. In PA, the lack of acid induces continuous gastrin cell activation and is responsible for the subsequent gastrin hypersynthesis and secretion. In ZES, hypergastrinemia causes hypertrophy of the oxyntic mucosa, which, in addition, displays hyperplasia of parietal and mucus cells. In both diseases, hypergastrinemia also induces the hyperproliferation of enterochromaffin-like endocrine cells in the fundic mucosa, which can offer all aspects from hyperplasia, then dysplasia, until true carcinoid tumor. The influence of antisecretory treatments and MEN 1 in the ZES as well as that of several other factors and antrectomy in PA on the behavior of the different gastric cells is evoked. Finally, the role that gastrin and its receptor play in the maintenance of the normal development of gastric mucosa and gastric acid secretion is emphasized by results observed in gene knockout models.
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Affiliation(s)
- T Lehy
- INSERM U.10, Hopital Bichat, F.75877 Paris Cedex 18, France
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Delle Fave G, Marignani M, Moretti A, D'Ambra G, Martino G, Annibale B. Hypergastrinemia and enterochromaffin-like cell hyperplasia. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 1998; 71:291-301. [PMID: 10461360 PMCID: PMC2578981 DOI: pmid/10461360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
UNLABELLED The enterochromaffin-like (ECL) cells, the most frequent endocrine cells of the oxyntic mucosa of the stomach, are under the trophic stimulus of gastrin. These cells undergo a hyperplastic increase in variety of hypergastrinemic diseases. The most widely accepted nomenclature for the description of hyperplastic proliferation has been retrospectively arranged in a sequence presumed to reflect a temporal evolution of the proliferative process. A comparative, prospective study aimed to verify, in human hypergastrinemic diseases such as atrophic body gastritis (ABG), Zollinger-Ellison syndrome (ZES) and antral gastrin cell hyperfunction (AGCH), the effect of exposure of ECL cells to different pattern of gastrin hypersecretion, is lacking. To this purpose, we studied a series of consecutive patients with ABG, ZES and AGCH at the time of first diagnosis. MATERIAL AND METHODS The patients included in this study (124 ABG, 18 ZES and 10 AGCH) were selected on the basis of two previously performed screening studies aimed to diagnose these diseases. All patients at the time of diagnosis underwent gastroscopy, with multiple biopsies of the gastric body mucosa for the evaluation of qualitative pattern of ECL cells hyperplasia, and basal fasting gastrin determination. A sample of hypergastrinemic patients from each group was further investigated by meal-stimulation of gastrin secretion and quantitative morphometry for CgA positive gastric body endocrine cells. RESULTS AGCH patients showed only the normal or simple hyperplasia pattern. In the ZES group, simple and linear grades accounted for 38.4 percent and 46.1 percent, respectively. MEN-I patients showed only these two patterns. The majority of ABG patients showed the presence of micronodular pattern (59.7 percent). A correlation analysis between fasting gastrin levels and grade of hyperplasia (r = 0.5580, p < 0.0001), indicates that the greater the gastrin levels, the higher is the degree of severity of ECL hyperplasia pattern. In conclusion, our data support the role of gastrin as the selective contributor to the progression of ECL cell hyperplasia in humans.
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Affiliation(s)
- G Delle Fave
- Cattedra di Gastroenterologia, Università La Sapienza, Rome, Italy
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Tari A, Hamada M, Kamiyasu T, Fukino Y, Sumii M, Haruma K, Sumii K, Inoue M, Kajiyama G. Effects of pirenzepine on omeprazole-induced hypergastrinemia and acid suppression in peptic ulcer patients. J Gastroenterol 1996; 31:167-170. [PMID: 8680534 DOI: 10.1007/bf02389513] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Omeprazole effectively suppresses acid secretion, resulting in the long-term elevation of intragastric pH and serum gastrin level. Pirenzepine has been reported to inhibit gastrin secretion. This study was carried out to examine the effects of additional pirenzepine treatment on the hypergastrinemia and gastric acid suppression induced by omeprazole. Concentrations of serum gastrin and plasma somatostatin were measured in 28 peptic ulcer patients before treatment, after omeprazole treatment (20 mg/day) for 2 weeks, and after omeprazole and pirenzepine (100 mg/day) treatment for 2 weeks. The acid inhibitory effect of pirenzepine treatment in addition to omeprazole was evaluated by 24-h intragastric pH measurement in six healthy volunteers. Serum gastrin level was increased significantly, to 2.4-fold the pretreatment level, by omeprazole treatment. Additional treatment with pirenzepine suppressed serum gastrin level to 0.6-fold the omeprazole-treatment level. The serum somatostatin level was not altered significantly either by omeprazole treatment or by omeprazole and pirenzepine treatment. In healthy volunteers whose pH 3 holding time on 24-h intragastric pH monitoring was 70% by omeprazole treatment, omeprazole and pirenzepine treatment markedly increased the pH 3 holding time, to 89%. These findings suggest that pirenzepine is useful in reducing the undesirable effects of omeprazole-induced hypergastrinemia, i.e., the excessive trophic effect of omeprazole on the acid-secreting part of the stomach and the overstimulation of acid secretion. The additional pirenzepine treatment is also effective in suppressing acid secretion.
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Affiliation(s)
- A Tari
- Department of Internal Medicine, Hiroshima Red Cross Hospital, Japan
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Abstract
OBJECTIVE The author analyzed potential survival determinants in gastrinoma to characterize a possible uniform staging system and to determine whether complete surgical resection improves expected survival. SUMMARY AND BACKGROUND DATA Gastrinoma is an indolent yet malignant neuroendocrine tumor. The associated gastric acid hypersecretion can be controlled medically. Staging of gastrinoma is inconsistent and the role of surgical resection controversial. METHODS Seventy-four patients with gastrinoma with a minimum 5-year follow-up were assessed. Cox's proportional hazards regression model was used to examine the association of risk factors with survival. RESULTS The following factors had no effect on survival: age at diagnosis, sex, presence of lymph node metastases, associated multiple endocrine neoplasia, and method of ulcer treatment. The three unique determinants of survival were primary tumor size (relative risk, 1.534; p = 0.0005), liver metastases (relative risk, 2.947; p = 0.0209), and complete surgical resection (relative risk, 0.163; p = 0.0076). On the basis of these risk factors, a uniform staging system is proposed and predictive survival curves developed. CONCLUSIONS The primary determinants of survival in gastrinoma are the size of the primary tumor and liver metastases. Complete surgical resection reduces mortality, regardless of other factors.
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Affiliation(s)
- E C Ellison
- Department of Surgery, Ohio State University College of Medicine, Columbus, USA
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Cadiot G, Vissuzaine C, Potet F, Mignon M. Fundic argyrophil carcinoid tumor in a patient with sporadic-type Zollinger-Ellison syndrome. Dig Dis Sci 1995; 40:1275-8. [PMID: 7781446 DOI: 10.1007/bf02065537] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
In the Zollinger-Ellison syndrome, fundic argyrophil carcinoid tumors occur almost exclusively in the small subgroup of patients who also have multiple endocrine neoplasia type 1. In these patients, tumor development seems related to the same genetic alterations as those observed in other endocrine tumors related to multiple endocrine neoplasia type 1. We report here the second detailed case of a patient with sporadic Zollinger-Ellison syndrome who developed an argyrophil carcinoid tumor in nonatrophic fundic mucosa, suggesting that chronic hypergastrinemia may lead to fundic carcinoid development in nongenetically predisposed patients.
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Affiliation(s)
- G Cadiot
- Department of Gastroenterology, Bichat-Claude Bernard Hospital, Paris, France
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Ooi A, Ota M, Katsuda S, Nakanishi I, Sugawara H, Takahashi I. An Unusual Case of Multiple Gastric Carcinoids Associated with Diffuse Endocrine Cell Hyperplasia and Parietal Cell Hypertrophy. Endocr Pathol 1995; 6:229-237. [PMID: 12114744 DOI: 10.1007/bf02739887] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We describe a case of multiple gastric carcinoid tumors in a 47 year-old Japanese man. The patient had markedly elevated serum gastrin levels (>800 pg/mL), which were suppressed by secretin-pancreozymin administration. In the partial gastrectomy specimen, a total of 19 carcinoids arose from diffuse linear and micronodular hyperplasia of the oxyntic mucosal endocrine cells. The carcinoid cells were chromogranin A-positive. Except for a very small number of serotonin-positive cells in several carcinoids, none of the 19 reacted with a battery of antibodies to other bioactive neuroendocrine substances. The most prominent findings in this case were peculiar fundic glands that were distended with a proteinaceous substance and lined with large hypertrophic parietal cells. At the ultra-structural level, these cells showed poorly developed intracytoplasmic canaliculi and vesicotubular profiles, yet their large cytoplasm had numerous mitochondria. On the basis of our histological and ultrastructural findings we suggest that an intrinsic HCI secretion abnormality of the parietal cells may be responsible for the patient's hypergastranemia. Since there have been no reports on similar parietal cells changes, it is possible that our case may represent a pathological entity not previously described.
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Spencer CM, Faulds D. Lansoprazole. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy in acid-related disorders. Drugs 1994; 48:404-30. [PMID: 7527761 DOI: 10.2165/00003495-199448030-00007] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Lansoprazole is a benzimidazole derivative that effectively decreases gastric acid secretion, regardless of the primary stimulus, via inhibition of gastric H+,K(+)-adenosine triphosphatase (ATPase). It provides effective symptom relief and healing of peptic ulcer and reflux oesophagitis after 4 to 8 weeks of therapy and appears to prevent recurrence of lesions when administered as maintenance therapy. When administered at therapeutic dosages, lansoprazole produced higher healing rates than ranitidine or famotidine in patients with duodenal and gastric ulcers. Lansoprazole heals duodenal ulcers more rapidly than ranitidine or famotidine. Relief of ulcer symptoms in lansoprazole recipients is at least equivalent to, and tends to be more rapid than, that in patients receiving histamine H2-receptor antagonists. In comparisons with omeprazole 20 mg/day, lansoprazole 30 mg/day produced duodenal ulcer healing more rapidly and reduced ulcer pain to a greater extent at 2 weeks, but overall healing rates were similar after 4 weeks of therapy. At therapeutic dosages, lansoprazole produces superior healing and symptom relief of reflux oesophagitis in comparison with ranitidine, and it tends to relieve heartburn more effectively than omeprazole, although both agents produce equivalent healing. Healing of peptic ulcers or reflux oesophagitis refractory to histamine H2-receptor antagonists occurs after 8 weeks in the majority of patients treated with lansoprazole, and lansoprazole and omeprazole demonstrate similar efficacy in patients with refractory peptic ulcers. In patients with Zollinger-Ellison syndrome, lansoprazole effectively controls mean basal gastric acid output. Lansoprazole is generally well tolerated in clinical trials. The incidence of adverse effects is similar to that of omeprazole, ranitidine and famotidine in comparative studies. Combination therapy with lansoprazole and antibacterial agents such as amoxicillin, tinidazole, roxithromycin and/or metronidazole appears to eradicate Helicobacter pylori in 22 to 80% of patients with this organism. Limited data also suggest that lansoprazole may have superior activity against H. pylori in comparison with omeprazole, although the clinical relevance of this preliminary finding requires further confirmation. Thus, lansoprazole may be considered as alternative to existing antisecretory agents available for the treatment of acid-related disorders, particularly because it may provide more rapid healing and relief of symptoms.
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Affiliation(s)
- C M Spencer
- Adis International Limited, Auckland, New Zealand
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Abstract
Omeprazole, a gastric acid pump inhibitor, dose-dependently controls gastric acid secretion: the drug has greater antisecretory activity than histamine H2-receptor antagonists. Omeprazole 20 to 40 mg/day is more effective than histamine H2-receptor antagonists in the short term treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis. Available data suggest that omeprazole 10 to 40 mg/day is also more effective than ranitidine in the maintenance therapy of duodenal ulcer and reflux oesophagitis. The drug is also effective in patients with duodenal ulcer, gastric ulcer or reflux oesophagitis poorly responsive to histamine H2-receptor antagonists. The efficacy of omeprazole 20 mg/day appears to be similar to that of lansoprazole 30 mg/day in the short term treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis. However, most available studies have been reported in abstract form only, and 2 of 3 studies in patients with duodenal ulcer have shown greater healing rates at 2 (but not 4) weeks with lansoprazole. Helicobacter pylori eradication decreases duodenal ulcer relapse rates and appears to be associated with improved duodenal ulcer healing rates. Evidence also suggests that H. pylori eradication is associated with reduced gastric ulcer relapse rates. Omeprazole monotherapy may suppress but does not eradicate H. pylori infection. Eradication rates with omeprazole 20 or 40 mg twice daily plus amoxicillin usually up to 2 g/day (3 g/day in a few studies) for 2 weeks appear to be similar to those of standard triple therapy (bismuth salt plus metronidazole, plus tetracycline or amoxicillin) or omeprazole plus clarithromycin, although eradication rates vary widely. Omeprazole plus amoxicillin appears to be better tolerated than triple therapy and represents a first-line treatment alternative in patients with H. pylori-associated peptic ulcer disease. Omeprazole plus amoxicillin plus metronidazole appears to be more effective than omeprazole plus amoxicillin in patients with metronidazole-sensitive H. pylori infection. Omeprazole remains a treatment of choice in patients with Zollinger-Ellison syndrome. The dosages should be adjusted according to individual response. However, relatively low dosages of 10 to 40 mg/day may be sufficient in some patients. The drug has also shown promise in the treatment of children with severe reflux oesophagitis, in patients with reflux oesophagitis and coexisting systemic sclerosis, and in the prevention of aspiration pneumonia. Evidence suggests that omeprazole is more effective than ranitidine in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced gastric damage who continue to take NSAIDs, especially in patients with large gastric ulcers; however, completion of ongoing studies is required to verify this.(ABSTRACT TRUNCATED AT 400 WORDS)
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Affiliation(s)
- M I Wilde
- Adis International Limited, Auckland, New Zealand
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Ruszniewski P, Ramdani A, Cadiot G, Lehy T, Mignon M, Bonfils S. Long-term treatment with octreotide in patients with the Zollinger-Ellison syndrome. Eur J Clin Invest 1993; 23:296-301. [PMID: 8354336 DOI: 10.1111/j.1365-2362.1993.tb00777.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
This study reports the effects of 4 and 5-year treatment with octreotide (200 micrograms sc bid) in the Zollinger-Ellison syndrome (ZES). No symptoms related to acid hypersecretion were observed in the four patients throughout the study, and upper GI endoscopy was normal. Basal acid output (BAO) measured 12 h after injection, was below 10 mmol h-1 in three to four patients and previous ranitidine treatment was discontinued. In the fourth case (pretreatment BAO value: 115 mmol h-1), BAO progressively decreased to 42 mmol h-1 after 5 years of octreotide treatment. At the end of the study, serum gastrin levels were 58.5% (30-68) of the pretreatment values and two patients had normal gastrin levels. Peak acid output (PAO) decreased markedly after 2, 4 and 5 years, by 68% (35-89) suggesting that octreotide had exerted an antitrophic effect on parietal cell mass. Diffuse hyperplasia of fundic argyrophil cells present in two patients before octreotide, decreased during the treatment. Mean argyrophil cell density for all patients was not significantly modified. Antral gastrin-cell density was in the normal range. No long-term side effect of octreotide treatment was observed. Although octreotide may not be considered as a substitute for benzimidazoles in the treatment of ZES, its specific properties may be of therapeutic benefit in some ZES patients.
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