Zollinger Ellison Syndrome


Article Author:
Min Cho


Article Editor:
Anup Kasi


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/4/2019 12:42:12 PM

Introduction

Zollinger-Ellison syndrome (ZES) is a group of symptoms comprised of severe peptic ulcer disease, gastroesophageal reflux disease (GERD), and chronic diarrhea caused by a gastrin-secreting tumor of the duodenum or pancreas (gastrinoma triangle) that results in increased stimulation of acid-secreting cells of the stomach.[1][2] Gastrinoma is a functional neuroendocrine tumor that secretes gastric acid which causes ZES.[3] The earlier misconception was that the location of gastrinoma is in the pancreas. However, gastrinomas occur in duodenum more than pancreas by three times especially in the first portion of the duodenum.[4] There are other non-neuroendocrine tumors secreting gastrin, but not adequate amounts to cause significant symptoms.[1] Gastrinoma causing ZES occurs sporadically in about 80% of cases and is reported to be 20% to 25% as multiple endocrine neoplasia type 1 (MEN1) from multiple reports in the literature.[4][5] Approximately 50% of patients with MEN1 have ZES; therefore, MEN1 must be included in a workup if ZES is highly suspicious.[4] It takes an average of 8 years from the start of symptoms to diagnosis due to the widespread use of proton pump inhibitors (PPIs).[4][5] One study of two referral centers in Italy and the United States showed a 62% decrease in referrals and diagnosis of ZES compared to a time when PPIs were used less frequently.[5][6]

In 1955, ZES made first its appearance in Annals of Surgery as a case series compiled by two surgeons from Ohio State University, Dr. Robert M. Zollinger and Edwin H. Ellison. Both cases had ulcers at the upper jejunum with excess gastric acid production refractory to medical therapy and surgical therapy including gastrectomy. The ultimate finding that led to ZES with hypersecretion, hyperacidity, and recurrent peptic ulceration was a non-beta cell islet tumor of the pancreas.[7] The pioneer case series induced enough interest to lead to the publication of multiple studies that recognize the connections between gastrinoma and ZES.

Etiology

An ectopic neuroendocrine gastrin-secreting tumor that stimulates the acid-secreting cells of the stomach causes ZES. Gastrin results in gastrointestinal mucosal ulceration.[8]

Epidemiology

On top of the increased use of PPIs in modern time and difficulty diagnosing ZES early, only 0.1% to 1% of patients with peptic ulcer disease (PUD) have ZES.[5][2] There is a report that an estimated 25% to 30% of patients with ZES have MEN1 which is a group of hyperplasia and/or tumors of pituitary, parathyroid, and pancreatic islet cells. Therefore, patients with ZES from MEN1 could cause hypersecretion of gastric acid from hypercalcemia [8][9] An article by Epelboym and Mazeh in 2014 displayed the difficulty in estimating the incidence because of overlap between ZES and PUD, and an accurate incidence cannot be determined, but gastrinomas are found in every 0.1 to 3 persons per million.[10] There are more females than males developing ZES, and all age groups reported having ZES.[10][11]

Pathophysiology

Most common symptoms including abdominal pain, diarrhea, and heartburn are caused by excess gastrin secretion from gastrinoma.[5] [12] An article by Arnold described the trophic effect of excess gastrin as "increased fundic mucosal thickness, increased parietal cell mass, prominent gastric folds, and proliferation of gastric enterochromaffin-like (ECL) cells."[12] Usually, gastric acid secretion is controlled by negative feedback mechanisms by somatostatin released by gastric D cells to maintain gastric acid homeostasis to maintain pH in the stomach properly.[8] However, due to unopposed gastrin release by the neuroendocrine tumor, gastrinoma results in severe PUD because of excess gastric acid secretion to the post-bulbar regions of the duodenum from esophagus via trophic effect of gastrin on ECL and parietal cells.[8][13][14]

History and Physical

The most common finding from ZES is abdominal pain, followed by diarrhea and heartburn. The patients can present initially with long periods of persistent symptoms due to unopposed gastrin secretion from gastrinoma. Malabsorption takes effects from hypersecretion of acid, and patients can present with weight loss and chronic diarrhea. Helicobacter pylori testing is negative, and despite taking PPIs, many patients will continue to have symptoms.[5][15] Because gastrinoma also presents as part of MEN1, some patients have a family history of endocrinopathy or some history of refractory PUD at an early age.[5][15][16] Examples of endocrinopathy include hypercalcemia and kidney stones from parathyroid hyperplasia and/or neoplasm.

Evaluation

To perform laboratory tests to diagnose ZES accurately, patients must stop the use of PPIs for at least 1 week, and cease using H2-receptor antagonist for 48 hours.[4][5] An initial test involves measuring fasting serum gastrin levels. This test has 99% sensitivity, and patients with gastrinoma will have a gastrin level greater than 100 pg/ml. The test is diagnostic if the level is greater than 1000 pg/ml.[4][5][10] However, the fasting gastrin level can normalize after parathyroidectomy in patients with MEN1 and gastrinoma resection even though the ZES is not fully cured.[5] Basal acid output test has 98% sensitivity and a level greater than 5 mEq per hour if the patient had gastrinoma resection or greater than 15 mEq per hour for those who did not. Gastric pH would be less than equal to 2. One can perform a secretin stimulation test which measures fasting serum gastrin level at 2 to 15 minutes after intravenous secretin administration. A level greater than or equal to 200 pg/ml indicates ZES and has 85% to 87% sensitivity.[4][5][10] 

If ZES is suspicious, screening for MEN1 needs to performed by ordering serum calcium, parathyroid hormone level, prolactin, and pancreatic polypeptide.[10] MEN1 is strongly suspected if patients indeed have primary hyperparathyroidism and parathyroidectomy is recommended.[4]

Imaging studies are recommended to localize gastrinoma or to evaluate any metastases. Usually, noninvasive imaging is done to assess the extent of the primary tumor or metastases. Use invasive imaging to locate the tumors before the surgery. CT and MRI detect up to 3 cm of mass but are not reliable if the mass is less than 3 cm. Somatostatin receptor scintigraphy (SRS) is known to be more sensitive than conventional imaging studies including CT and MRI and have higher specificity to detect extrahepatic gastrinoma. SRS is also called octreoscan and involves using indium-labeled octreotide that has a strong affinity for type 2 somatostatin receptors which are expressed on cells of gastrinoma. Positron emission tomography is used to assess metastasis to other body organs. Invasive modalities include an endoscopic ultrasound to evaluate pancreas more closely and an esophagogastroduodenoscopy (EGD) to visually assess any abnormalities.[4][5][10]

Treatment / Management

Before the discovery of H2-receptor antagonist in 1970s and PPIs in 1980s,  the only reasonable option to treat ZES was a total gastrectomy.[1] The dose of PPIs such as oral omeprazole and intravenous pantoprazole must be adjusted to normalize basal acid output levels to less than 15 mEq per hour and less than 5 mEq per hour for those who had surgery to decrease acid secretion. Eighty milligrams of pantoprazole by mouth twice daily is the typical dose. Patients should take this on an empty stomach.[4] For those rare patients who cannot tolerate PPIs, an H2-receptor antagonist is an option.[1] 

Hyperparathyroidism from MEN1 causes hypercalcemia which can exacerbate the symptoms because hypercalcemia increases gastrin levels. Therefore, subtotal parathyroidectomy must precede the resection of the primary tumor which can result in better symptoms control and may normalize abnormal gastrin levels.[4] Because patients with ZES and MEN1 have multiple tumors that have a very low cure rate, a tumor is only to be resected if the size is greater than 2 cm. Surgical exploration is an option in patients with sporadic gastrinomas because of a high propensity for the tumor to metastasize to the liver, lymph nodes, and distant organs. Those with advanced disease needs to have multidisciplinary rounds for more nonsurgical options including chemotherapy with everolimus, sunitinib, somatostatin analogues, interferon, chemoembolization, radioembolization, and radiofrequency ablation.[1][4][10]

Differential Diagnosis

Differential diagnosis of hypergastrinemia includes vagotomy, PUD secondary to Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs (NSAIDs) use, gastric outlet obstruction, renal insufficiency, short bowel syndrome, and autoimmune gastritis (Type A).[8][12]

Etiology of peptic ulcer includes overuse of NSAIDs such as ibuprofen and aspirin. A clinician may not be able to distinguish abdominal pain from excess acids and ulcers from PUD and ZES, but ZES cause more diarrhea and esophageal disease.[5] Helicobacter pylori produce urease which acts near G cells and causes urea hydrolysis and alkalization, affecting D cells and diminishing somatostatin cell release secondary to inflammation. Gastric outlet obstruction causes antral distention which activates parietal cells via acetylcholine.[8] Patients with chronic kidney disease or end-stage renal disease and undergoing dialysis have elevated serum gastrin. Gastrin clears through the kidney, and renal insufficiency will prevent the kidney from working properly. One study revealed an increase in gastric cell growth in a rat model with uremia resulted from proton back-diffusion in the stomach causing less mucosal barrier protection.[8][17][18][19]  Gastric outlet obstruction causes distension of antrum which activates parietal cells via acetylcholine and results in hypergastrinemia.[8]

Prognosis

Because ZES involves gastrinoma, one has to evaluate prognosis based cancer stage. About 60% to 90% of gastrinomas are malignant with metastasis to the lymph nodes, liver, or distant organs. Fifty percent of pancreatic gastrinomas have a 50% incidence, and 10% of duodenal gastrinomas have a 10% incidence to the liver. Metastasis to the liver has a direct effect in overall survival as pancreatic gastrinomas have lower long-term survival rates than duodenal gastrinomas. The patients with liver metastases have a 15% 10-year survival after the surgery, but those without liver metastases have a 95% 20-year survival which is a significant finding.[4]

On the other hand, duodenal gastrinomas have a higher incidence of lymph node metastases than pancreatic gastrinomas, 70% versus 40% respectively. However, lymph node involvement did not show a decrease in survival without liver metastases.[4][20][21]

Complications

Complications from acid secretion can cause bleeding and perforation of GI tracts including esophagus, stomach, and duodenum.[5][15] Significant complication includes death from the surgery when the plan is to remove gastrinoma or other cancers from MEN1.

Deterrence and Patient Education

Clinicians must educate patients to comply with taking PPIs to control symptoms for ZES. Patient must not only take medications as instructed but follow up for laboratory tests to assess the effectiveness of the medications. This is very important to reduce the recurrence and complications from ZES. Although the cure rate, especially with MEN1, is low, patients need to be encouraged to follow up with proper physicians and seek help if needed.

Pearls and Other Issues

ZES is caused by gastrinoma which causes trophic effects of gastrin hypersecreting gastric acid. It can cause severe abdominal pain from multiple ulcers in the esophagus, stomach, and duodenum, diarrhea, and heartburn. PPIs have been the main therapy to control the symptoms. MEN1 is associated with ZES due to gastrinoma being a part of MEN1. However, the cure rate is slim, and surgical resection is not an ideal option. If surgical exploration is indicated, then managing hyperparathyroidism including subtotal hyperparathyroidectomy must precede actual gastrinoma resection to control symptoms. There is a high propensity of sporadic gastrinoma metastasizing to the liver, lymph nodes, and a surgeon must evaluate distant organs and those that found to have sporadic gastrinoma for surgery. If the disease has already metastasized and the patient is not a surgical candidate, there are multiple options including embolizations and chemotherapy.

Enhancing Healthcare Team Outcomes

Interprofessional communication between a primary care physician, gastroenterologists, surgeons, oncologists, pharmacists, nurses, and laboratory personnel is necessary for professionals to stay on the same page to treat ZES. Diagnosing ZES can be challenging with the wide use of PPIs for heartburn, but patients may suffer from unexplained chronic diarrhea, malabsorption, and even dysphagia from esophagus damage secondary to excess gastric acid secretion. A multidisciplinary approach with a social worker and a case manager is needed if patients have a hard time coping with situations that endanger social life. Because ZES is hard to cure, patients must stay on PPIs to control symptoms, and it could be daunting. Continuous support must entail support not only from medical professions but also from close family members and friends. (Level III)


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Zollinger Ellison Syndrome - Questions

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Which is false about the Zollinger Ellision syndrome (ZES)?



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Which of the following is false about Zollinger Ellison syndrome (ZES)?



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A 45-year-old male presents to the emergency department with a 4-month history of mild epigastric discomfort and diarrhea. He said the abdominal pain was constant but also aggravated by food. Over the counter medications were ineffective for his stomach pain. He was prescribed antihistamine type 2 blockers which failed to resolve his condition. Blood work revealed that the patient had a marked elevation in the fasting serum gastrin levels (520 pg/ml, normal <150 pg/ml). What is the appropriate next step?



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Which of the following is a symptom of Zollinger Ellison syndrome?



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Which of the following is the most effective to treat Zollinger-Ellison syndrome?



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A patient has multiple gastric ulcers, hypercalcemia, and failure to respond to Helicobacter pylori therapy. What is the most likely diagnosis?



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Which condition is associated with rapid gastric emptying?



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A patient has recurrent ulcer disease and diarrhea and is suspected to have Zollinger-Ellison syndrome (gastrinoma). A screening test of fasting serum gastrin is positive, so a secretin stimulation test is performed. Which of the following would confirm the diagnosis?



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Which drug is used for treating Zollinger-Ellison syndrome?



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A patient has recurrent ulcer disease and diarrhea and is suspected to have Zollinger-Ellison syndrome (gastrinoma). Which of the following would confirm the diagnosis?



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A 62-year-old female is diagnosed with a Helicobacter pylori infection that is causing peptic ulcer disease. She is appropriately treated with two antibiotics and a proton pump inhibitor, which is continued long term. The patient's symptoms recur. Stool tests and a urea breath test are negative for recurrence of H. pylori, so a repeat endoscopy is done. Persistent and new ulcers are noted. Fasting gastrin and basal acid secretion are elevated. What is the best next step?



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A patient with upper abdominal pain and diarrhea does not respond to proton pump inhibitors. Upper endoscopy shows multiple ulcers in the duodenum. Biopsies are negative for Helicobacter pylori. What is the most likely etiology?



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Zollinger-Ellison syndrome is best treated with which drug as a first-line agent?



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Which of the following is a viable treatment option for Zollinger-Ellison syndrome?



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A 45-year-old male presents with increased tenderness in the epigastric region. He lacks an appetite and has experienced weight loss over the past few months. His vital signs are within in the normal reference range. Initial diagnostic testing reveals a fasting serum gastrin level of more than 1000 picograms/mL. Which of the following would be expected upon secretin administration?



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A 50-year-old male with a past medical history of refractory peptic ulcer disease presents with heartburn, abdominal pain, and chronic diarrhea. Lab results and endoscopic findings confirm Zollinger-Ellison syndrome. What lab result is expected to be seen in this patient?



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A 45-year-old female who dealt with severe abdominal pain and acid reflux symptoms presented to a gastroenterologist from a primary care physician's referral. A patient has been on proton pump inhibitor for several years with minimal improvement. Esophagogastroduodenoscopy was performed in the past which showed multiple stomach and duodenal ulcers with esophagitis. The patient underwent further workup including fasting serum gastrin level and basal acid output for Zollinger-Ellison syndrome and found to have the disease. Which of one the following statements has a direct effect on overall survival rate?



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Zollinger Ellison Syndrome - References

References

Gastric Hypersecretory States: Investigation and Management., Phan J,Benhammou JN,Pisegna JR,, Current treatment options in gastroenterology, 2015 Dec     [PubMed]
Norton JA,Foster DS,Ito T,Jensen RT, Gastrinomas: Medical or Surgical Treatment. Endocrinology and metabolism clinics of North America. 2018 Sep;     [PubMed]
Cingam SR,Karanchi H, Gastrinoma 2018 Jan;     [PubMed]
ZOLLINGER RM,ELLISON EH, Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Annals of surgery. 1955 Oct;     [PubMed]
Roy PK,Venzon DJ,Feigenbaum KM,Koviack PD,Bashir S,Ojeaburu JV,Gibril F,Jensen RT, Gastric secretion in Zollinger-Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis--a prospective NIH study of 235 patients and a review of 984 cases in the literature. Medicine. 2001 May;     [PubMed]
Krampitz GW,Norton JA, Current management of the Zollinger-Ellison syndrome. Advances in surgery. 2013;     [PubMed]
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Corleto VD,Annibale B,Gibril F,Angeletti S,Serrano J,Venzon DJ,Delle Fave G,Jensen RT, Does the widespread use of proton pump inhibitors mask, complicate and/or delay the diagnosis of Zollinger-Ellison syndrome? Alimentary pharmacology     [PubMed]
Arnold R, Diagnosis and differential diagnosis of hypergastrinemia. Wiener klinische Wochenschrift. 2007;     [PubMed]
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Quintero E,Ohning GV,Del Rivero M,Wong HC,Walsh JH,Guth PH, Gastrin mediates the increase in gastric cell growth in uremic rats. The American journal of physiology. 1995 Apr;     [PubMed]
Quintero E,Kaunitz J,Nishizaki Y,De Giorgio R,Sternini C,Guth PH, Uremia increases gastric mucosal permeability and acid back-diffusion injury in the rat. Gastroenterology. 1992 Dec;     [PubMed]
Vinik A,Perry RR,Hughes MS,Feliberti E, Multiple Endocrine Neoplasia Type 1 2000;     [PubMed]
Epelboym I,Mazeh H, Zollinger-Ellison syndrome: classical considerations and current controversies. The oncologist. 2014 Jan;     [PubMed]
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. 2006 Nov;     [PubMed]
Pisegna J,Holtmann G,Howden CW,Katelaris PH,Sharma P,Spechler S,Triadafilopoulos G,Tytgat G, Review article: oesophageal complications and consequences of persistent gastro-oesophageal reflux disease. Alimentary pharmacology     [PubMed]
Pisegna JR, The effect of Zollinger-Ellison syndrome and neuropeptide-secreting tumors on the stomach. Current gastroenterology reports. 1999 Dec;     [PubMed]
Roy PK,Venzon DJ,Shojamanesh H,Abou-Saif A,Peghini P,Doppman JL,Gibril F,Jensen RT, Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine. 2000 Nov;     [PubMed]
Jensen RT, Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. Journal of internal medicine. 1998 Jun;     [PubMed]
Sutliff VE,Doppman JL,Gibril F,Venzon DJ,Yu F,Serrano J,Jensen RT, Growth of newly diagnosed, untreated metastatic gastrinomas and predictors of growth patterns. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1997 Jun;     [PubMed]
Roland CL,Bian A,Mansour JC,Yopp AC,Balch GC,Sharma R,Xie XJ,Schwarz RE, Survival impact of malignant pancreatic neuroendocrine and islet cell neoplasm phenotypes. Journal of surgical oncology. 2012 May;     [PubMed]

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