Hypochlorhydria and Achlorhydria Are Associated With False-Positive Secretin Stimulation Testing for Zollinger-Ellison Syndrome

Shah, Pari; Singh, Maneesh H.; Yang, Yu‐Xiao; Metz, David C.

doi:10.1097/mpa.0b013e3182847b2e

Cited by 24 publications

(14 citation statements)

References 30 publications

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“…Gastrinomas overexpress somatostatin receptors e.g., SSTR2, permitting their diagnosis and treatment with somatostatin analogues 45 , which presumably would suppress elevated PKA activity in the tumors. Although the secretin stimulation test used to diagnose gastrinomas is imperfect 46 , the secretin receptor is coupled to heterotrimeric G proteins that stimulate adenylate cyclase, increase cAMP and activate PKA 32, 47 . Thus PKA signaling appears to play a central role in the biology of gastrinomas akin to our observed regulation of gastrin in enteric glial cells.…”

Section: Discussionmentioning

confidence: 99%

Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells

et al. 2017

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Background The Multiple Endocrine Neoplasia, type 1 (MEN1) locus encodes the nuclear tumor suppressor protein menin. MEN1 mutations frequently cause neuroendocrine tumors (NETs) such as gastrinomas, remarkable for their predominant duodenal location and local metastasis at the time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner’s glands. We show here that loss of menin in enteric glial cells induces gastrin expression. Aim To determine how menin regulates gastrin gene expression and induces the generation of submucosal gastrin-expressing cell hyperplasia. Methods Primary enteric glial cultures were generated from the Villin-Cre:Men1FL/FL:Sst−/− mice with or without inhibition of gastric acid using omeprazole. In addition, primary enteric glial cells from wild type mice were treated with gastrin and were separated into nuclear and cytoplasmic fractions. Forskolin and H89 treatments were used to activate or inhibit protein kinase A activity. Immunoprecipitation with menin or ubiquitin was used to demonstrate posttranslational modification of menin. Primary glial cells were treated with Leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. Results Gfap+ enteric glial cells expressed gastrin de novo through a feedforward PKA-dependent mechanism. Gastrin-induced nuclear export of menin through Cckbr-mediated PKA activation. Once exported menin was ubiquitinated and degraded by the proteasome. Gfap and other enteric glial markers co-localized with gastrin in human duodenal gastrinomas. Conclusion Collectively, these results suggest that MEN1-associated gastrinomas, which develop in the submucosa might arise from enteric glial cells through hormone-dependent PKA signaling that abrogates menin function leading to hypergastrinemia and associated sequelae.

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Section: Discussionmentioning

confidence: 99%

Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells

et al. 2017

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“…Another approach recently used in the literature to attempt to establish the diagnosis of ZES without assessing gastric acidity, is to use of the secretin test. While the secretin test , when performed prior to PPIs in patients with gastric pH≤2, has high sensitivity for detecting ZES [94% using a criterion of ≥120 pg/ml increase [77]] and high specificity [100%, using a criterion of ≥120 pg/ml increase [77]], several studies report that it can give false positive tests if performed in patients with achlorhydria [77, 116] or hypochlorhydria, such as when taking PPIs [79, 154]. Therefore, if it is used in a patient taking PPIs, the secretin test result may not be valid.…”

Section: Discussion and Proposal Of New Criteria To Support Thementioning

confidence: 99%

“…Second, recent studies [53, 54] have documented that >50% of the currently used gastrin assays are inaccurate. Third, the roles of supplementary testing with secretin testing [12, 45, 77–79] and, in occasional patients, a full gastric analysis [10, 12, 13, 45] (Table 1), are now unclear for different reasons. Secretin was not available for several years; however, synthetic human secretin, which is fully biologically active [80] is now available (ChiRhoStim, NDC #67066-005-01, Burtonsville, MD).…”

Section: What Are the Current Controversies In The Diagnosis Of Zes?mentioning

confidence: 99%

“…It has an important clinical use in the diagnosis of ZES in some patients, as reviewed here and below, and hopefully it will become available again in Europe and be a useful tool for ZES diagnosis there again. Another factor contributing to the limited use of secretin testing is the fact that it can give false-positive results in patients with achlorhydria [77, 116] or in patients taking potent antisecretory drugs such as PPIs [79]. Therefore, as with FSG determinations, secretin testing is best performed early on when the patient is first seen and not yet taking any PPIs or after the PPI is held to allow for the development of an acidic gastric pH (which, as described above, needs to be performed with caution, best done in a specialty unit.).…”

Section: Examination Of the Basis For The Current Controversies Imentioning

confidence: 99%

“… (1) ZES patients post incomplete gastrinoma resection [51], MEN1/ZES patients post effective parathyroidectomy (usually 3.5–4 gland resection) for hyperparathyroidism [52], and uncommonly other ZES patients (0–2%) [42] can have a normal FSG. (2) The role of imaging for diagnosis of ZES has not been systematically studied and is not clearly defined at present. (3) Achlorhydria is a well-recognized cause of false-positive secretin testing [79, 116] …”

Section: Tablementioning

confidence: 99%

See 2 more Smart Citations

Diagnosis of Zollinger–Ellison Syndrome in the Era of Ppis, Faulty Gastrin Assays, Sensitive Imaging and Limited Access to Acid Secretory Testing

Metz

Cadiot

Poitras

et al. 2017

Int. J. Endo. Oncol.

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In recent years the diagnosis of Zollinger-Ellison syndrome (ZES) has become increasingly controversial with several new approaches and criteria proposed, differing from the classical biochemical criterion of inappropriate hypergastrinemia (i.e., hypergastrinemia in the presence of hyperchlorhydria) (Table 1). These changes have come about because of the difficulty and potential dangers of stopping proton pump inhibitors (PPIs) for gastric acid analysis; the recognition than many of the current assays used to assess gastrin concentrations are unreliable; the development of sensitive imaging modalities that detect neuroendocrine tumors (NETs) including an increasing number of the primary gastrinomas; the increased use of percutaneous or endoscopic ultrasound (EUS)-directed biopsies/cytology and the general lack of availability of acid secretory testing. In this article we will discuss the basis for these controversies, review the proposed changes in diagnostic approaches and make recommendations for supporting the diagnosis of ZES in the modern era.

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Zollinger–Ellison Syndrome

Jensen

2015

Yamada' S Textbook of Gastroenterology

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Hypochlorhydria and Achlorhydria Are Associated With False-Positive Secretin Stimulation Testing for Zollinger-Ellison Syndrome

Cited by 24 publications

References 30 publications

Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells

Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells

Diagnosis of Zollinger–Ellison Syndrome in the Era of Ppis, Faulty Gastrin Assays, Sensitive Imaging and Limited Access to Acid Secretory Testing

Zollinger–Ellison Syndrome

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