Ellison Syndrome Research Articles

Evolution of the doctrine of Zollinger-Ellison syndrome. Literature review

Zollinger–Ellison syndrome (ZES) is a rare pathology that does not have specific clinical manifestations and is not always diagnosed in time. This is attributed to doctors’ insufficient awareness of this pathology and the limited availability of the necessary examination methods. Foreign literary sources on this problem are analysed. Historical data regarding the discovery of this pathology and the origin of the syndrome’s name are provided. The epidemiology of the disease is highlighted. The most characteristic clinical manifestations and possible complications of ZES are described in detail. The characteristic changes in gastric acid production associated with this pathology and their diagnostic value (sensitivity and specificity) are presented. At the same time, indicators of both basal and maximal stimulated gastric acid production are significantly increased. The most important stage in the examination of patients with suspected ZES is the determination of blood gastrin levels. At the same time, it is shown that it is not always possible to make definitive judgements in support of ZES based on gastrin indicators. An absolute criterion in favor of ZES is fasting gastrin values of 1000 pg/ml or more. When gastrin levels are less than this indicator, tests using secretin or calcium gluconate have significant diagnostic value. In these circumstances, tests with secretin or calcium gluconate are mandatory. The information on the possible localization of gastrin, the incidence of malignant transformation, and the mechanism of metastasis is given. Methods of determining gastrin localization, sensitivity, and specificity are described in detail. Based on the findings, a differentiated treatment strategy for patients with ZES is provided. Indications and contraindications for surgical and medical treatment of patients with ZES are given. The prospects of a new treatment direction ‑ the use of targeted radiotherapy ‑ are shown. These patients require constant monitoring by a gastroenterologist and a surgeon and periodically undergo the necessary examinations.

Natural language processing assisted detection of inappropriate proton pump inhibitor use in adult hospitalised patients

ObjectivesTo establish a clinical application monitoring system for proton pump inhibitors (PPI-MS) and to enhance the detection and intervention of inappropriate PPI use in adult hospitalised patients.MethodsNatural language processing technology...

Primary hyperparathyroidism and concurrent severe hypergastrinemia in a dog

AbstractA 7‐year‐old, neutered, male beagle dog was presented for the investigation of hyporexia, vomiting and polyuria‐polydipsia. Ionised hypercalcaemia secondary to primary hyperparathyroidism was diagnosed. The dog developed a perforated gastric ulcer associated with marked hypergastrinemia. The dog died of cardiopulmonary arrest 6 days after admission. Gastrinoma can be associated with Zollinger–Ellison syndrome, characterised by the presence of peptic ulcers and hypergastrinemia. Concurrent primary hyperparathyroidism and gastrinoma is a typical presentation of multiple endocrine neoplasia type 1 syndrome, a human syndrome that causes the development of several tumours in endocrine glands; but has never been described in dogs. Hypergastrinemia secondary to hypercalcaemia, and unrelated to gastrinoma, has also been described in humans, but not in dogs. This case reports the atypical co‐occurrence of primary hyperparathyroidism and severe hypergastrinemia, which could be a consequence of hypercalcaemia, or be secondary to a concurrent disease such as an undetected gastrinoma.

Zollinger–Ellison syndrome within the framework of multiple neoplasia syndrome type 1: Description of the clinical case

Multiple endocrine neoplasia syndrome type 1 (MEN-1, Vermeer syndrome) is an autosomal dominant hereditary syndrome characterized by mutations in the MEN1 gene. The manifestation of the syndrome is associated with hyperplasia and tumor transformation of several endocrine glands: tumors of the parathyroid glands, pituitary gland, pancreas, adrenal glands. Within the framework of MEN-1, Zollinger–Ellison syndrome may develop – a clinical syndrome caused by hypergastrinemia, the source of which is gastrin-producing tumors of the pancreas and other localizations, resulting in hypersecretion of hydrochloric acid. This leads to the appearance of peptic ulcers of the duodenum and stomach, refractory to treatment and complicated by bleeding and stenosis. The article describes a clinical case of a young patient with the classic triad of components of MEN-1 syndrome, including multiple gastrinomas with frequent recurrences of gastric ulcer and duodenal ulcer.

Formulation development and evaluation of omeprazole buccal tablets

Omeprazole is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upper gastrointestinal bleeding in people who are at high risk. The Mucoadhesive buccal tablets were prepared by direct compression method using Sodium Alginate, HPMC K4M and SCMC as mucoadhesive polymer. The compatibility studies of drug and excipients were performed by FT-IR spectroscopy. After examining the flow properties of the powder blends the results are found to be within prescribed limits and indicated good flowing property, hence it was subjected to tablet compression. The tablets were evaluated for post compression parameters like weight variation, hardness, thickness, friability, drug content uniformity, Surface pH, in-vitro studies like drug release. Formulation (F4) containing HPMC K4M in the ratio of (1:1) showed maximum drug release of 99.54% in 8 hrs. The drug content of shown highest of 99.61 %, Surface pH was found to be 6.05. All the evaluation parameters given the positive results and comply with the standards. The results indicate that the mucoadhesive buccal tablets of Omeprazole may be good choice to bypass the extensive hepatic first pass metabolism with an improvement in the bioavailability of Omeprazole through buccal mucosa.

Sporadic and MEN1-related gastrinoma and Zollinger–Ellison syndrome: differences in clinical characteristics and survival outcomes

PurposeGastrinoma with Zollinger–Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features.MethodsConsecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort.ResultsOf 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger (p = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES (p = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p = 0.034). At univariate-logistic regression, age at diagnosis (p = 0.01, OR = 1.1), G3 grading (p = 0.003, OR = 21.3), Sp-ZES (p = 0.02, OR = 0.3) and presence of extrahepatic metastases (p = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age (p = 0.04, OR = 1.0), size (p = 0.039, OR = 1.0), G3 grade (p = 0.008, OR = 14.6) and extrahepatic metastases (p = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases (p = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS (p = 0.0227). After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively.ConclusionMEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response.

Radiological Features of Zollinger-Ellison Syndrome: A Report of Two Cases.

Hypersecretion of gastrin from duodenal or pancreatic gastrinomas results in a rare clinical entity called Zollinger–Ellison syndrome (ZES). It mostly presents with abdominal pain and diarrhea. ZES may be sporadic or occur in association with multiple endocrine neoplasia type 1. Usually, ZES manifests between 20 and 50 years.We report two cases of patients who presented with abdominal pain, vomiting, watery diarrhea, and significant weight loss.

Formulation and Characterization of Sustained Release Matrix Tablet of Pantoprazole

Pantoprazole is a proton pump inhibitor prodrug used in the treatment of gastric, duodenal ulcers and gastro esophageal reflux disease (GERD), Zollinger- Ellison syndrome. This is the most popular drug used in cure and maintenance therapy of peptic ulcer along with antibiotics. It suppresses the acid production by inhibiting the H+ K+ ATPase. Pantoprazole must be absorbed in the gastrointestinal tract and because it is unstable under acidic conditions, enteric delivery systems are required. The purpose of this study was to prepare matrix tablet using eudragit Rs 100, eudragit S100, and HPMC. On the basis of above result the formulation showed satisfactory result as it has the maximum release i.e. F5 66.50%in 10 hrs. Result of our study suggest that the matrix tablet containing pantoprazole may be suitable for the anti ulcer drug.

Pancreaticoduodenectomy Is the Best Surgical Procedure for Zollinger-Ellison Syndrome Associated with Multiple Endocrine Neoplasia Type 1.

Simple SummaryApproximately 30% of patients with multiple endocrine neoplasia type 1 (MEN1) develop the Zollinger–Ellison syndrome (ZES), caused by solitary or multiple duodenal gastrinomas. Its management, especially regarding indication, timing, and type of surgery, is highly controversial. Therefore, the present study evaluated the long-term outcomes of pancreaticoduodenectomy (PD) versus non-PD resections in MEN1-ZES with regard to biochemical cure and quality of life. We found in a series of 35 patients that initial PD is the superior surgical procedure for MEN1-ZES, leading to long-term cure in about 80% of patients, fewer duodenopancreatic reoperations and an acceptable quality of life. Based on the results of this study, MEN1-ZES should be considered a surgically curable disease.Aim: The aim of this research was to evaluate the long-term outcome of pancreaticoduodenectomy (PD) versus other duodenopancreatic resections (non-PD) for the surgical treatment of the Zollinger–Ellison syndrome (ZES) in patients with multiple endocrine neoplasia type 1 (MEN1). Methods: Prospectively recorded patients with biochemically confirmed MEN1-ZES who underwent duodenopancreatic surgery were retrospectively analyzed in terms of clinical characteristics, complications, cure rate, and long-term morbidity, including quality of life assessment (EORTC QLQ-C30). Results: 35 patients (16 female, 19 male) with MEN1-ZES due to duodenopancreatic gastrinomas with a median age of 42 (range 30–74) years were included. At the time of diagnosis, 28 (80%) gastrinomas were malignant, but distant metastases were only present in one (3%) patient. Eleven patients (31.4%) underwent pancreatoduodenectomy (PD) as the initial procedure, whereas 24 patients underwent non-PD resections involving duodenotomy with gastrinoma excision, enucleation of the pNEN from the head of the pancreas, and peripancreatic lymphadenectomy, either with or without distal pancreatectomy (i.e., either Thompson procedure, n = 12, or DUODX, n = 12). There was no significant difference in perioperative morbidity and mortality between the two groups (p ≥ 0.05). One (9%) patient of the PD group required reoperation for recurrent or metastatic ZES compared to eight (22.8%) patients of the non-PD resection groups. After a median follow-up time of 134 months (range 6–480) nine of 11 (82%) patients in the PD group, two of 12 (16%) patients in the Thompson procedure group, and three of 12 (25%) patients in the DUODX group had normal serum gastrin levels. In addition, the global health QoLScore was better in the PD group (76.9) compared to the Thompson procedure (57.4) and DUODX (59.5) groups. Conclusions: Initial PD seems to be the superior surgical procedure for MEN1-ZES, resulting in a long-term cure rate of about 80%, fewer duodenopancreatic reoperations, and an acceptable quality of life.

On the history and some characteristics of neuroendocrine tumors of the gastrointestinal tract. Neuroendocrine tumors of the pancreas. Part 2

The literature review presents the analysis of numerous studies that have formed the basis for creating ideas about the diffuse endocrine system,namely existence of the cellular accumulations and individual cells that produce various hormones and biologically active substances in addition to the main endocrine glands. Several types of endocrine cells with these functionshave been established, in particular, in the organs of the gastrointestinal tract, starting from the esophagus and up to the terminal parts of the large intestine. Most of them are contained in the pancreas, antrum of the stomach, duodenum, the initial part of the intestine, in the liver. Excessive secretory activity of these cells can cause the development of pathological clinical syndromes, characterized by the effects of the corresponding hormones. The tumors or diffuse hyperplasia of the corresponding cellsmay present morphological substrate of such syndromes. The author considers the pancreas as an integral part of the diffuse endocrine system, as specific endocrine functions in it perform numerous accumulations (islets of Langerhans) or individual cells. The review of the numerous neuroendocrine tumors of the gastrointestinal tract examines in detail the characteristics of some of them in historical and clinical aspects, in particular Zollinger—Ellison syndrome as the most common and well-studied tumor. Glucagonoma is also considered as a neuroendocrine tumorderived from α-cells of the pancreas, is a kind of insulinoma antagonist, as it secretes an excess of the hormone glucagon, causing the development of hyperglycemic clinical syndrome in contrast to hypoglycemic, caused by insulin. It is a rare tumor and its consideration after insulinoma can be explained by the antagonistic nature of the action of hormones produced by these tumors. In the group of neuroendocrine tumors of the pancreas, glucagonoma follows the frequency of insulinoma and gastrinoma.

Usefulness of computed tomography during arteriography in a selective arterial calcium agent injection test for pancreatic gastrinoma: a case description.

Pancreatic gastrinoma is a rare pancreatic neuroendocrine tumor with an incidence of about 0.5–21.5 cases per million people worldwide. The most common sites are the duodenum (75%), pancreas (20%), and other organs (5%). Gastrinomas are malignant in about 60–90% of cases (1-5). Malignant gastrinomas originating beneath the duodenal mucosa often metastasize to the liver, even if the tumor diameter is ≤1 cm. Therefore, in patients with gastrinoma and Zollinger–Ellison syndrome, it is important to determine the number and site(s) of gastrinoma(s), as well as the presence or absence of liver metastases. However, the detection sensitivity of computed tomography (CT) and magnetic resonance imaging is about 10–50%, that of angiography is 20–50%, and that of somatostatin receptor scintigraphy is 30–70%. Tumor size is strongly correlated with the detection sensitivity of any examination modality, and tumors of <1 cm in diameter are often difficult to detect (1,2). Therefore, the selective arterial calcium agent injection (SACI) test was developed as an effective method to detect small gastrinomas (2,6,7). In the SACI test, calcium gluconate is injected via a microcatheter into selected arterial branches to stimulate gastrin secretion from the gastrinoma located in the corresponding arterial territory. Generally, calcium gluconate is selectively injected into the gastroduodenal artery (GDA), superior mesenteric artery (SMA), distal or proximal portion of the splenic artery (distal SpA, proximal SpA), and the proper hepatic artery (PHA). The subsequent increase in the serum gastrin level is monitored using blood samples taken from the hepatic vein before and at 30, 60, 90, and 120 s after the injection. The location of the gastrinoma is determined based on a significant increase in serum gastrin levels in response to calcium gluconate (maximum serum gastrin level after calcium injection/serum gastrin level before calcium agent injection; with a median change of about 4.21 times baseline) (8). However, there are two limitations of the SACI test. First, the distribution of calcium varies between individual patients due to anatomical differences in the pancreatic arterial branches and the arterial territories. Second, there are many false positives following the injection of calcium gluconate into the GDA (median change of 4.15 times the baseline value) because calcium gluconate may stimulate normal gastrin-secreting cells in the gastric prepylorus and duodenal bulbus (8,9). It is possible to visualize the distribution of calcium following its injection by performing CT during arteriography (CTA). Here, we report a case in which the SACI test was combined with CTA for the diagnosis of a gastrinoma located in the pancreatic head and to exclude the presence of liver metastases.

A rare case of a metastatic neuroendocrine tumor of the pancreas

Aim. To study a rare sporadic case of metastatic gastrinoma associated with mutations in the MEN1 and TSC2 genes in a 25-year-old male. Materials and methods . A retrospective analysis of the history of a 25-year-old patient with sporadic gastrinoma with a highly aggressive clinical course and high metastatic potential was performed. Sequencing of the DNA extracted from the surgical tumor biopsy was performed on the Illumina NextSeq 550 sequencer (Illumina Inc., USA) with the mean coverage of at least 100× using the AmpliSeq target panel for Illumina Comprehensive Cancer Panel for studying exons of 409 genes, mutations in which are associated with oncopathology. Results. The article presents the results of complex diagnosis and treatment of metastatic gastrinoma using modern locoregional therapy and drugs from the group of somatostatin analogues. Using next generation sequencing and Sanger sequencing, sporadic mutations in the MEN1 and TSC2 genes with pronounced clinical significance were identified in the extracted DNA. Conclusion. The identified mutations, being the drivers of the tumor process, apparently determined the atypical development of the presented clinical case – the sporadic Zollinger – Ellison syndrome. Complete morphological and immunohistochemical validation of the neuroendocrine tumor before treatment determined a successful treatment strategy, including the use of somatostatin analogues in adjuvant and neoadjuvant therapies in combination with chemoembolization of hepatic metastases.

Zollinger ellison syndrome due to primary nodal gastrinoma located outside the limits of the conventional gastrinoma triangle: report of a case

Primary nodal gastrinoma is a rare entity and the diagnosis is often contemplative when no other non - nodal primary site can be identified despite thorough investigations and operative exploration. Here we report one such case wherein a primary nodal gastrinoma was diagnosed as an entity of exclusion. Additionally, the location of the disease outside the confines of the conventional gastrinoma triangle further contributes to the rarity of the presentation. A young male patient had presented to us with history of multiple operations in the past for recurrent upper abdominal pain presumably consequential to peptic ulcer disease viz a trucal vagotomy and gastrojejunostomy, duodenal ulcer perforation surgery and a cholecystectomy. CT scan and endoscopic USG showed a preaortic calcified node located outside the limits of the gastrinoma triangle. A raised serum gastrin level and an endoscopic guided FNAC confirmed the diagnosis of a gastrinoma. A 68 Ga-DOTANOC PET CT revealed an exclusive nodal uptake with no discenable primary lesion. Normalization of gastrin levels after removal of the involved pre-aortic node further pointed to the diagnosis of primary nodal gastrinoma. A high index of clinical suspicion is warranted especially in a history of multiple surgeries for recurrent upper abdominal pain and location of the lesion outside the confines of the ‘Gastrinoma Triangle’ should not be deterrent for the diagnosis.

Current Potential of Pantoprazole in Treatment and Prevention of Gastrointestinal Diseases

Aim. An outline of the current potential of pantoprazole in treatment and prevention of upper gastrointestinal diseases.Key points. Pantoprazole is widely applied in gastroesophageal reflux, peptic ulcer disease, Zollinger—Ellison syndrome and for Helicobacter pylori eradication. It minimally inhibits the CYP2C19 isoenzyme involved in the metabolism of many drugs. Pharmacokinetics of pantoprazole conditions a weaker drug interaction compared to other proton pump inhibitors (PPIs), which enables its use for gastrointestinal bleeding prevention in patients receiving dual antiplatelet therapy. The new coronaviral pandemic of COVID-19 urges the selection of PPIs that minimise the drug interference, such as pantoprazole, in therapy and prevention of acid-related upper gastrointestinal diseases. Pantoprazole has a good tolerance and low side effect rate.Conclusion. Pantoprazole is considered among optimal PPIs for efficacy, safety and adherence on the basis of clinical trials for treatment and prevention of gastrointestinal diseases, systematic reviews and meta-analyses.

A novel rp-hplc method for determination of esomeprazole in pharmaceutical dosage forms in human plasma: A pilot stress degradation study

Esomeprazole, an proton pump inhibitor used for the remedy of acid reflux disorders including healing and maintenance of erosive esophagitis, gastroesophageal reflux disease and peptic ulcer disease. It is utilized in a prolonged treatment of pathological hypersecretory conditions such as Zollinger -Ellison syndrome. In this study, a novel RP-HPLC method was developed for the determination of esomeprazole both in API and tablets (Esmoz (40mg)), Phenomenex Luna, 5μm C18 100 A° LC column (250X4.6mm) was used at 40°C. Isocratic elution was utilized with acetonitrile: water (96:4v/v) mixture. The flow rate was 1.0mL min-1 and UV detection was at 270nm. The RT value was observed at 3.713 minutes respectively. The developed method was validated according to ICH guidelines and found to be linear within the range of 100-500μg/mL. In similar lines, linearity was achieved by spiking esomeprazole in human plasma within the range of 20-80μg/mL. The developed method was accurate, precise, robust, and rapid. Hence it can be applied for both stability studies and routine quality control analyses.

Total gastrectomy for severe proton pump inhibitor-induced hypomagnesemia in a MEN1/Zollinger Ellison syndrome patient

We report here the first case of life-threatening hypomagnesemia in a Zollinger-Ellison syndrome patient with multiple endocrine neoplasia type 1 (MEN1) syndrome. The severe symptomatic hypomagnesemia proved to be due to proton pump inhibitors (PPIs), but withdrawal of PPIs led to early severe peptic complications despite a substitution by histamine H2-receptor antagonist therapy. Simultaneous management of life-threatening hypomagnesemia, severe gastric acid hypersecretion and MEN1-associated gastrinomas was complex. A total gastrectomy was performed in order to definitely preclude the use of PPIs in this frail patient who was not eligible for curative pancreatoduodenal resection.

S2202 Post-Surgical Presentation of Zollinger–Ellison Syndrome Following Resection of Endometrioid Neuroendocrine Tumor

INTRODUCTION: Zollinger–Ellison syndrome (ZE) may present as lymph node metastases at initial presentation. Here we report a case of ZE following resection of endometrioid small cell neuroendocrine carcinoma and endometrioid adenocarcinoma. CASE DESCRIPTION/METHODS: A 76-year-old Caucasian female presented with heavy vaginal bleeding. CT scan revealed an enlarged uterus measuring 6.2 × 5.4 cm. The patient underwent uneventful laparoscopic hysterectomy with bilateral salpingo-oophorectomy and bilateral sentinel lymph node dissection. Pathological examination demonstrated stage IB mixed endometrioid adenocarcinoma and small cell neuroendocrine carcinoma. Gastrin immunostaining was negative. The patient presented three months after completing chemotherapy (one month following radiation treatment with brachytherapy) with black stool in addition to watery diarrhea for more than 6 months. The patient denied taking aspirin or nonsteroidal anti-inflammatory drug and was not taking a proton pump inhibitor (PPI). Esophagogastroduodenoscopy (EGD) demonstrated multiple non-bleeding superficial gastric ulcers with clean ulcer bases (Forrest Class III) in the antrum and prepyloric region. No ulcers were identified in the duodenum. An elevated serum gastrin level (538 pg/mL) was noted the day after EGD while not on PPI therapy. Somatostatin receptor-based imaging (Ga-68 Dotatate- PET/CT) revealed avid left paraesophageal node uptake measuring 11 × 8 mm. Stool helicobacter pylori antigen test was negative. Serum calcium (9.2 mg/dL), renal function and PTH were within normal limits. After five months, follow up EGD demonstrated two persistent (2-3 mm) clean based ulcerations in the posterior gastric wall. Gastric fluid demonstrated pH of 1 despite Pantoprazole 40 mg twice a day for 4 months. Endoscopic ultrasound examination demonstrated an ill-defined 14 × 7 mm heterogenous lymph node in the region of the lymph node noted on PET scan, which was sampled by fine needle aspiration, revealing scant lymphoid tissue insufficient for pathologic diagnosis. DISCUSSION: Here the diagnosis of ZE was based on a combination of persistent gastric ulcerations in the presence of elevated serum gastrin, gastric pH < 2, and somatostatin receptor-based imaging, despite our being unable to identify a primary lesion. Our case illustrates the importance of utilizing multiple modalities in establishing a presumptive diagnosis of ZE.Figure 1.: Multiple clean based ulcers in the gastric antrum and prepyloric region.Figure 2.: Persistent clean based ulcerations in the gastric antrum.Figure 3.: Left paraesophageal node uptake (Ga-68 Dotatate- PET/CT).

Primary intracardiac gastrinoma causing Zollinger-Ellison syndrome.

Primary intracardiac gastrinoma causing Zollinger-Ellison syndrome.

Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome.

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.

2714 Famotidine-Induced Hypomagnesemia Leading to Hypocalcemia

INTRODUCTION: Famotidine is a long-acting histamine H2 receptor antagonist that is indicated for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease and Zollinger- Ellison syndrome. It is considered to have an excellent safety profile with only a few side effects like constipation, diarrhea, and headache. We present a case of famotidine induced hypomagnesemia and functional hypoparathyroidism causing hypocalcemia. CASE DESCRIPTION/METHODS: A 55-year-old female with a past medical history of GERD was admitted to hospital due to increased lethargy, confusion, and muscle cramps for last 15 days. These muscle cramps affected functions of her hands and legs, causing multiple falls. She was taking famotidine 20 mg twice a day for the last two years. Her vital signs were stable. On exam, alert and oriented 2x, dry skin, positive Chvostek’s and Trousseau's sign. Initial blood work showed sodium 141 mmol/L, BUN 13 mg/dL, creatinine 0.7 mg/dL, calcium 5.7 mg/dL, magnesium 0.55 mg/dL, phosphorus 3.4 mg/dL. She was treated with multiple doses of intravenous (IV) 2 g magnesium sulfate and 1 g of calcium gluconate. Further work showed low PTH but normal PTHrP, vitamin D (25) and vitamin D (1,25). Her calcium and magnesium level normalized with IV therapy, so she was discharged home on oral electrolyte supplements. She followed up with her family doctor with a repeat blood work and noted to have very low calcium and magnesium so admitted to hospital. Extensive workup including 24 hours urine calcium and magnesium was unimpressive. She was treated with IV therapy and discharged to follow up with nephrology in the clinic with a repeat blood work. Her famotidine was discontinued on discharge. Her calcium and magnesium level remained normal, and few weeks later, oral electrolyte supplements were discontinued. DISCUSSION: This is the first reported case of famotidine induced hypomagnesemia and functional hypoparathyroidism causing hypocalcemia. Famotidine might cause impaired absorption of magnesium, leading to hypomagnesemia and functional hypoparathyroidism. Patients being started on a H2 receptor antagonist for the long-term course should have a baseline serum calcium and magnesium level and periodic monitoring as well. The optimal timing for monitoring levels is unknown, but annual monitoring (sooner if the patient develops symptoms) may be reasonable. Long-term use of famotidine should be considered in the differential diagnosis for hypomagnesemia and hypocalcemia.