Zollinger-Ellison Syndrome

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 times and the resultant difficulty in 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, a group of hyperplastic cells or tumors of the pituitary, parathyroid, and pancreatic islet cells. Therefore, patients with ZES from MEN1 could cause hypersecretion of gastric acid from hypercalcemia.[8][9] Epelboym and Mazeh, in 2014, presented the difficulty in estimating the incidence because of the overlap between ZES and PUD, and an accurate incidence cannot be determined. Still, gastrinomas are found in every 0.1 to 3 persons per million.[10] More females than males are 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] 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 cells."[12] Usually, gastric acid secretion is controlled by negative feedback mechanisms by somatostatin released by gastric D cells to maintain gastric acid homeostasis and proper pH.[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 the esophagus via the trophic effect of gastrin on enterochromaffin-like and parietal cells.[8][13][14]

History and Physical

The most common symptom of 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 a gastrinoma. Malabsorption leads to hypersecretion of acid, and patients can present with weight loss and chronic diarrhea. Helicobacter pylori testing is negative; many patients continue to have symptoms despite taking PPIs.[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 or neoplasm.

Evaluation

For laboratory tests to accurately diagnose ZES, patients must stop using PPIs for at least 1 week or cease using H2-receptor antagonists for 48 hours.[4][5] An initial test involves measuring fasting serum gastrin levels. This test has 99% sensitivity, and patients with gastrinoma have a gastrin level greater than 100 pg/ml. The test is diagnostic if the level exceeds 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 the clinician suspects ZES, screening for MEN1 needs to be performed by ordering serum calcium, parathyroid hormone level, prolactin, and pancreatic polypeptide.[10] MEN1 is strongly suspected if patients 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. Imaging can locate the tumors before the surgery. CT and MRI detect up to 3 cm of mass but are unreliable if the mass is less than 3 cm. Somatostatin receptor scintigraphy is known to be more sensitive than conventional imaging studies, including CT and MRI, and has higher specificity to detect extrahepatic gastrinoma. Somatostatin receptor scintigraphy involves indium-labeled octreotide with a strong affinity for type 2 somatostatin receptors expressed on gastrinoma cells. Positron emission tomography is used to assess metastasis to other body organs. Invasive modalities include an endoscopic ultrasound to evaluate the pancreas more closely and an esophagogastroduodenoscopy to assess any abnormalities visually.[4][5][10]

Treatment / Management

Before the discovery of H2-receptor antagonists in the 1970s and PPIs in the 1980s, total gastrectomy was the only reasonable option to treat ZES.[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 with prior 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 symptom control and may normalize abnormal gastrin levels.[4] Because patients with ZES and MEN1 have multiple tumors with a very low cure rate, a tumor is only resected if the size is greater than 2 cm. Surgical exploration is an option in patients with sporadic gastrinomas because of the high propensity for the tumor to metastasize to the liver, lymph nodes, and distant organs. Those with advanced disease need interprofessional rounds for more nonsurgical options, including chemotherapy with everolimus, sunitinib, somatostatin analogs, interferon, chemoembolization, radioembolization, and radiofrequency ablation.[1][4][10](B3)

Differential Diagnosis

Differential diagnosis of hypergastrinemia includes vagotomy, PUD secondary to Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs use, gastric outlet obstruction, renal insufficiency, short bowel syndrome, and autoimmune gastritis (Type A).[8][12] The etiology of peptic ulcers includes the overuse of nonsteroidal anti-inflammatory drugs such as ibuprofen and aspirin. A clinician may be unable to distinguish abdominal pain from excess acids and ulcers from PUD and ZES, but ZES causes more diarrhea and esophageal disease.[5] Helicobacter pylori produces 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 prevents the kidney from working properly. One study revealed increased gastric cell growth in a rat model with uremia resulting from proton back diffusion in the stomach, causing less mucosal barrier protection.[8][17][18][19] Gastric outlet obstruction causes distension of the antrum, which activates parietal cells via acetylcholine and produces hypergastrinemia.[8]

Prognosis

Because ZES involves gastrinoma, one must evaluate the 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 in the liver. Metastasis to the liver directly affects 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 consist of bleeding and perforation of GI tracts, including the esophagus, stomach, and duodenum.[5][15] Significant complications include death from surgery when the plan is to remove gastrinoma or other cancers from MEN1.