ZOLLINGER–ELLISON SYNDROME

Severe peptic ulcer diathesis secondary to gastric acid hypersecretion due to unregulated gastrin release from a non-β cell endocrine tumor (gastrinoma) Initially, ZES was typified by aggressive and refractory ulceration in which total gastrectomy Today it can be cured by surgical resection in up to 40% of patients

Epidemiology The incidence is 0.1–1% of PUD Males than females, ages 30 and 50 classified into sporadic tumors (more common) and multiple endocrine neoplasia (MEN) type 1 The widespread availability and use of PPIs has led to a decreased patient referral for gastrinoma evaluation, delay in diagnosis diagnosis delayed for 6 or more years after symptoms consistent

Pathophysiology Hypergastrinemia an autonomous neoplasm is responsible for the clinical manifestations Gastrin stimulates acid secretion through gastrin receptors on parietal cells and by inducing histamine release from ECL cells Gastrin also has a trophic action on gastric epithelial cells

Longstanding hypergastrinemia … Longstanding hypergastrinemia ….. markedly increased gastric acid secretion through both parietal cell stimulation and increased parietal cell mass The increased gastric acid output leads to peptic ulcer diathesis, erosive esophagitis, and diarrhea

Tumor Distribution Extrapancreatic … 80% of these tumors are found within the gastrinoma triangle (confluence of the cystic and CBD superiorly, junction of the second and third portions of the duodenum inferiorly, and junction of the neck and body of the pancreas medially) Duodenal tumors(the most common nonpancreatic lesion); between 50 and 75% are found here

Duodenal tumors are smaller, slower growing, and less likely to metastasize than pancreatic lesions Less common extrapancreatic sites include stomach, bones, ovaries, heart, liver, and lymph nodes

More than 60% of tumors are considered malignant, with up to 30–50% of patients having multiple lesions or metastatic disease at presentation Histologically, gastrin-producing cells appear well- differentiated, expressing endocrine markers (chromogranin, neuron-specific enolase)

Clinical Manifestations Gastric acid hypersecretion is responsible for the signs and symptoms ZES Peptic ulcer(the most common) occurring in >90% Initial presentation and ulcer location (duodenal bulb) may be indistinguishable from common PUD

Clinical situations suspicion of gastrinoma : ulcers in unusual locations (second part of the duodenum and beyond), ulcers refractory to standard medical therapy, ulcer recurrence after acid-reducing surgery, ulcers presenting with frank complications (bleeding, obstruction, and perforation), or ulcers in the absence of H. pylori or NSAID ingestion

Esophageal symptoms up to two-thirds of patients with ZES, with a spectrum ranging from mild esophagitis to frank ulceration with stricture and Barrett’s mucosa Diarrhea, the next most common clinical manifestation, is found in up to 50% of patients Although diarrhea often occurs concomitantly with acid peptic disease, it may also occur independent of an ulcer

Etiology of diarrhea is multifactorial, marked volume overload to the small bowel, pancreatic enzyme inactivation by acid, and damage of the intestinal epithelial surface by acid The epithelial damage can lead to maldigestion and malabsorption of nutrients The diarrhea may also have a secretory component due to the direct stimulatory effect of gastrin on enterocytes or. co-secretion of additional hormones such as vasoactive intestinal peptide

Gastrinomas presence of MEN 1 syndrome in ~25% of patients Ad , involves primarily three organ : the parathyroid glands (80–90%), pancreas (40–80%), and pituitary gland (30–60%) caused by inactivating mutations of the MEN1 tumor suppressor gene found on 11q13…encodes Menin…important role in DNA replication and transcriptional regulation mutations in 70–90% of typical MEN 1 cases

Diagnosis, patient has tumors in two of the three endocrine organs (parathyroid, pancreas/duodenum, or pituitary) or has a family history of MEN 1 and one of the endocrine organ tumors the hyperparathyroidism … hypercalcemia …. stimulatory effect on gastric secretion …direct effect on ulcer disease parathyroidectomy ….Resolution of hypercalcemia …. reduces gastrin and gastric acid output in gastrinoma patient

the higher incidence of gastric carcinoid tumor development (as compared to patients with sporadic gastrinomas). Gastrinomas tend to be smaller, multiple, and located in the duodenal wall more than sporadic ZES Establishing the diagnosis of MEN 1 is critical ….. provide genetic counseling to the patient and his or her family and also to determine the recommended surgical approach

Diagnosis Biochemical measurements of gastrin and acid secretion The first step …. fasting gastrin level If present PPI…. Acid suppression…. Increased gastrin(hypergastrinemia) in normal individuals ….. Stop ppI one week before Fasting gastrin levels are usually <150 pg/mL

A normal fasting gastrin, on two separate occasions, especially if the patient is on a PPI, excludes this diagnosis. If fasting gastrin >150pg/ml …. Repeated gastrin(to confirm the clinical suspicion all gastrinoma patients will have a gastrin level >150–200 pg/mL

Multiple processes can elevated fasting gastrin level the most frequent are gastric hypochlorhydria and achlorhydria, with or without pernicious anemia , antisecretory agents , H. pylori infection , retained gastric antrum; G cell hyperplasia; gastric outlet obstruction; renal insufficiency; massive small- bowel obstruction; rheumatoid arthritis, vitiligo, diabetes mellitus, and pheochromocytoma

Fasting gastrin >10 times normal is highly suggestive of ZES The next step in diagnosis of gastrinoma is to assess acid secretion pH can be measured on gastric fluid obtained either during endoscopy or through nasogastric aspiration pH <3 is suggestive of a gastrinoma, but a pH >3 is not helpful in excluding the diagnosis…formal gastric acid analysis

Normal BAO in nongastric surgery patients is typically <5 meq/h BAO >15 meq/h in the presence of hypergastrinemia….ZES BAO/MAO ratio(using pentagastrin infusion)>0.6 … highly suggestive ZES Gastrin provocative tests(secretin stimulation test ,calcium infusion study) An increase in gastrin of ≥120 pg within 15 min of secretin injection has a sensitivity and specificity of >90% for ZES.

Tumor Localization Once a biochemical diagnosis has been confirmed … abdominal computed tomography (CT) scan, magnetic resonance imaging (MRI), or OctreoScan (depending on availability) to exclude metastatic disease EUS … pancreatic lesions Treatment

STRESS-RELATED MUCOSAL INJURY Shock, sepsis, massive burns, severe trauma, or head injury ….. acute erosive gastric mucosal changes or frank ulceration with bleeding Most commonly observed in the acid-producing (fundus and body) Most common presentation is GI bleeding, usually minimal but can be life threatening

Bleeding risk factors :Respiratory failure(mechanical ventilation) , underlying coagulopathy, multiorgan failure or severe burns, occur 48–72 h after the acute injury Histologically, stress injury does not contain inflammation or H.pylori; thus, “gastritis” is a misnomer

Pathogenesis : elevated gastric acid secretion in head trauma (Cushing’s ulcer) and severe burns (Curling’s ulcer), mucosal ischemia, breakdown of the normal protective barriers of the stomach, systemic release of cytokines, poor GI motility, and oxidative stress When acid inhibitors are used as prophylaxis drop in bleeding noted

ICU general management Improvement … ICU general management Improvement ….. decrease stress ulcer GI bleeding from 20–30% to <5% (prophylactic therapy) The mortality >40% with stress-induced clinically important GI bleeding and limited benefit of medical (endoscopic, angiographic) and surgical Preventive measures in highrisk patients (mechanically ventilated, coagulopathy,…)

Maintenance of gastric pH >3 Maintenance of gastric pH >3.5 : continuous infusion of H2 blockers or liquid antacids every 2–3 h , Sucralfate slurry (1 g every 4–6 h) but requires a gastric tube and may lead to constipation and aluminum toxicity and aspiration pneumonia, PPIs PPI not increase the risk of nosocomial infections, mortality, or prolonging ICU length of stay

Therefore, PPIs are choice for stress prophylaxis Oral PPI(best option if tolerate) ,parenteral administration If bleeding occurs ,endoscopy, intraarterial vasopressin, embolization …. Surgery