bubble_chart Overview

Gastrinoma is a non-beta islet cell tumor of the pancreas that produces large amounts of gastrin, leading to excessive gastric acid secretion and resulting in severe, refractory peptic ulcers.

bubble_chart Clinical Manifestations

Gastrinomas can occur at any age, most commonly between 20 and 40 years old, with 5% of cases occurring in children under 16 years old. The male-to-female ratio is 3:2. The main clinical symptoms are peptic ulcers and diarrhea.

(1) Peptic ulcers Over 90% of patients have ulcers. Gastrinomas secrete large amounts of gastrin, and the continuous stimulation by excessive gastrin leads to overproduction of gastric acid and pepsin, which digests the mucous membrane, resulting in ulcers. Ulcers mostly occur in the duodenum (60%) or the lesser curvature of the gastric antrum (10%). In 20% of cases, ulcers develop in atypical locations such as the lower esophagus, the second or third part of the duodenum, or the upper jejunum. Approximately 15% are multiple ulcers, often with one in the first part of the duodenum and the rest in the distal duodenum or jejunum. Patients exhibit ulcer symptoms, often with poor response to medical treatment, and have a high incidence of complications such as perforation and bleeding (60%). Ulcers are prone to recurrence after surgical treatment.

(2) Diarrhea 30% of patients experience diarrhea. In 7–10% of patients, diarrhea occurs without ulcer symptoms. Diarrhea occurs intermittently, with 5–6 watery bowel movements per day, sometimes presenting as steatorrhea, with large volumes of foul-smelling stool. Diarrhea results from the entry of large amounts of gastric acid into the small intestine, increasing intestinal fluid volume and acidifying the intestinal contents, which reduces the activity of pancreatic lipase and causes bile salts to precipitate in the intestine. Both factors impair fat digestion, emulsification, and absorption. Additionally, gastrin stimulates intestinal motility and affects the absorption of water and electrolytes. Diarrhea often leads to dehydration and hypokalemia.

bubble_chart Diagnosis

For patients with peptic ulcers, the possibility of gastrinoma should be considered under the following circumstances: ① duodenal ulcer patients under 20 years of age; ② accompanied by watery diarrhea or steatorrhea; ③ significantly increased gastric acid and gastrin secretion; ④ anastomotic ulcer after subtotal gastrectomy; ⑤ large or multiple ulcers or ulcers in uncommon locations, such as the distal duodenum or jejunum; ⑥ duodenal ulcer with hypercalcemia; ⑦ ineffective aggressive medical treatment; ⑧ rapid recurrence after vagotomy, with complications such as bleeding or perforation; ⑨ tumor in the duodenum detected by X-ray barium meal examination.

To confirm the diagnosis, the following further tests can be performed:

(1) Gastric juice analysis: Gastric juice analysis should be performed for all patients suspected of having gastrinoma. In patients with gastrinoma, the total nocturnal 12-hour gastric juice volume is >1000ml (normal <400ml), hourly gastric juice volume >200ml (general ulcer <100ml), basal acid output (BAO) >15mmol/h (normal 3.5mmol/h, duodenal ulcer <10mmol/h), and after stimulation with pentagastrin (6μg/kg IV), the maximum acid output (MAO) is only slightly higher than normal (30–40mmol/h), with BAO/MAO >0.6 (normal <0.2, duodenal ulcer >0.35). This is because in patients with gastrinoma, the blood gastrin concentration is already very high in the fasting basal state, and gastric acid secretion is highly stimulated, approaching the maximum level. Therefore, even with pentagastrin stimulation, the change is minimal.

(2) Gastrin measurement: The normal fasting serum gastrin level (radioimmunoassay) is 50–200pg/ml, duodenal ulcer patients have levels around 600pg/ml, while patients with gastrinoma have levels >500pg/ml, which can even reach 1000–2000pg/ml.

(3) Endoscopy and X-ray barium meal contrast may reveal: ① a large amount of gastric juice or abdominal mass in the stomach; ② gastrin has a trophic effect on the mucosa, leading to thickened and hypertrophic gastric mucosal folds, dilated duodenal and proximal jejunal lumens, and mucosal edema and hypertrophy; ③ ulcers in the first, second, or third part of the duodenum or jejunum; ④ tumor in the duodenum; ⑤ anastomotic ulcer in patients who have undergone subtotal gastrectomy.

bubble_chart Treatment Measures

Antacids and anticholinergic agents can only temporarily relieve symptoms and cannot control the progression of the disease. Patients often experience complications such as bleeding and perforation during treatment. Once complications occur, the mortality rate is very high.

In the past, due to the lack of effective medications, gastrinomas were treated surgically. Gastrinomas are often multiple or occult, making them difficult to detect during surgery. Superficial tumors were treated with simple tumor resection; deep tumors with distal pancreatectomy or pancreaticoduodenectomy; and when no tumor was found, blind distal pancreatectomy was performed, but symptoms often recurred postoperatively. Total pancreatectomy was poorly tolerated by patients, carried high risks, and resulted in complete loss of pancreatic function with severe sequelae. Malignant gastrinomas often had already metastasized by the time of surgery, making it impossible to completely remove all metastatic lesions even with total pancreatectomy. Moreover, metastatic lesions could also secrete large amounts of gastrin, causing symptoms and complications such as bleeding and perforation. Therefore, many surgeons advocated for total gastrectomy, as parietal cells are the target cells of gastrin. Total gastrectomy completely removes these target cells, eliminating gastric acid secretion even if tumors or metastatic lesions remain, thereby resolving symptoms and preventing complications. However, patients were often in poor general condition, and total gastrectomy was extensive, high-risk, and associated with numerous postoperative sequelae and severe nutritional disorders. In 1978, the H₂

receptor antagonist cimetidine was introduced. This drug significantly inhibits gastric acid secretion, controls gastrinoma symptoms, and prevents complications. Consequently, whether gastrinomas could be treated medically to avoid total gastrectomy became a contentious issue in the medical community.

Most surgeons still believed surgery was necessary for gastrin tumor diseases, citing the following reasons: ① Long-term high-dose cimetidine use could affect male hormone function, leading to adverse side effects such as gynecomastia, impotence, and mental confusion. ② Some patients developed resistance to the drug. ③ Many patients could not adhere to lifelong medication. Gastrinomas often cyclically reactivated, and patients would discontinue medication after symptom relief, only resuming treatment when ulcers recurred, causing bleeding or perforation. By then, their condition had significantly deteriorated, increasing the mortality rate of total gastrectomy. ④ Without surgery, patients with gastrinomas or malignant gastrin tumor diseases without metastasis would lose the opportunity for definitive treatment.

Generally, H₂ receptor antagonists are used first to observe the drug's efficacy. Unless liver metastasis is confirmed before surgery, and the drug is effective or the patient's overall condition contraindicates surgery, all cases should undergo exploratory surgery. Some patients who were initially in poor condition may improve with medication, making surgery no longer contraindicated. Patients with parathyroid adenoma should have the adenoma removed first. Preoperative correction of fluid and electrolyte imbalances and preparation for total gastrectomy are essential. During surgery, a comprehensive and thorough exploration should be conducted to determine the presence of tumors in the pancreas, duodenum, or gastric antrum, as well as metastasis to the liver or lymph nodes. For patients who do not respond to medication or require long-term continuous medication, especially young patients with multiple tumors or metastasis that cannot be completely resected, tumor resection and total gastrectomy should be performed whenever possible. Some advocate that for solitary tumors, particularly duodenal gastrinomas, total gastrectomy should not be performed; instead, tumor resection or distal pancreatectomy with selective vagotomy should be done. For cases where no tumor is found during surgery, only vagotomy should be performed, followed by postoperative H₂ receptor antagonist therapy and monitoring of serum gastrin levels. If symptoms recur and gastrin levels rise, total gastrectomy should then be performed. They believe that vagotomy can enhance the acid-suppressing effect of H₂ receptor antagonists. However, the cure rate of simple tumor resection is only 5%, and the enhancing effect of vagotomy on H₂ receptor antagonists remains uncertain. Therefore, many surgeons still recommend total gastrectomy for solitary tumors or cases where no tumor is found during surgery but preoperative diagnosis is definitive, serum gastrin levels are high, and gastric antrum G-cell hyperplasia is excluded. For elderly patients who respond well to medication and cannot tolerate total gastrectomy, selective vagotomy may be considered as an alternative. Any pyloric obstruction must be relieved. Experienced surgeons have a mortality rate of less than 3% for total gastrectomy. Unlike total gastrectomy for stomach cancer, if preoperative preparation is adequate, the surgery can be complication-free, with postoperative diarrhea controlled, weight gain, and rapid improvement in nutrition and overall condition. If no tumor is found during surgery, gastric antrum G-cell hyperplasia should be ruled out. If protein meal or secretin tests were not performed preoperatively and exclusion is not possible, subtotal gastrectomy or selective vagotomy with hemigastrectomy should be performed, followed by postoperative monitoring of gastrin levels. If levels remain high and symptoms recur, total gastrectomy should then be performed. Emergency total gastrectomy should be performed for complications such as bleeding or perforation caused by gastrinoma. In extremely high-risk cases, gastrointestinal reconstruction may be omitted after total gastrectomy, with a tube placed in the distal esophagus for drainage and a jejunostomy performed. Gastric-jejunal anastomosis can be done later when the patient's condition improves. Alternatively, intravenous cimetidine can be used to suppress gastric acid secretion, followed by perforation repair or bleeding vessel ligation.

bubble_chart Differentiation

The serum gastrin levels of duodenal ulcers and gastrinomas sometimes overlap. If the serum gastrin is at a borderline level (200–750 pg/ml), a stimulation test can be performed (measuring serum gastrin after a protein meal or intravenous injection of calcium gluconate or secretin). Many conditions other than gastrinoma can cause hypergastrinemia. Those not associated with high gastric acid secretion include: ① Atrophic gastritis (due to lack of gastric acid, the G cells in the gastric antrum release gastrin without inhibition). ② After gastric vagotomy (reduced gastric acid secretion stimulates the gastric antrum to secrete gastrin). These two can be distinguished from gastrinoma by gastric acid analysis. Conditions associated with high gastric acid secretion include: ① Renal failure (gastrin is primarily excreted by the kidneys, and poor renal function leads to gastrin accumulation); ② Hyperparathyroidism (hypercalcemia stimulates gastrin secretion); ③ Gastric antral G-cell hyperplasia; ④ Retained gastric antrum after gastric surgery (after partial gastrectomy with gastrojejunostomy, the antrum is isolated or residual antral mucosa remains), where the antrum is separated from gastric acid, which inhibits gastrin, but is exposed to alkaline duodenal fluid, leading to excessive gastrin secretion; ⑤ Ulcer disease with pyloric obstruction (gastric content retention in the antrum and gastric distension stimulate gastrin secretion). These five conditions can be distinguished from gastrinoma using stimulation tests.

In patients with duodenal ulcers and gastric antral G-cell hyperplasia, the antral G cells are stimulated by protein after a protein meal, leading to gastrin secretion and a significant rise in serum gastrin. In contrast, patients with gastrinoma (due to high gastric acid inhibiting gastrin release from the gastric mucosa) and those with retained antrum (where the residual antrum does not contact food) show little change in serum gastrin. Calcium is a strong stimulant for gastrin release in gastrinoma, and patients with gastrinoma exhibit a significant rise in serum gastrin after calcium injection, whereas those with duodenal ulcers or retained antrum do not. After secretin injection, patients with gastrinoma show a marked increase in serum gastrin, whereas those with duodenal ulcers, gastric antral G-cell hyperplasia, or retained antrum do not (Table 1).

Table 1 Differential Diagnosis of Gastrinoma

Test	Gastrinoma	G-cell Hyperplasia	Retained Antrum	Duodenal Ulcer
BAO (mmol/L)	>15	>15
BAO/MAO	>0.6	>0.6
Fasting Serum Gastrin (pg/ml)	>300	>300	>300	<160
Protein Meal	-	+	-	+
Calcium Gluconate	+		-	-
Secretin	+	-	-	-

Localization Diagnosis Once a gastrinoma is diagnosed, localization is necessary. Except for duodenal wall gastrinomas, barium meal X-ray examinations and endoscopy are of little help in localization. Due to the small size of the tumor, CT and B-ultrasound scans often fail to detect early-stage tumors. Gastrinomas in the pancreas are not highly vascularized, so selective angiography also yields unsatisfactory results. Percutaneous transhepatic portal vein catheterization, which involves drawing blood from various segments of the splenic vein draining the pancreas to measure serum gastrin levels, provides both localization and qualitative diagnostic value for pancreatic gastrinomas.