http://en.wikipedia.org/wiki/Zollinge-Ellison_syndrome

Gastrinoma (Zollinger-Ellison Syndrome) (Zes) 해리슨 18판

A gastrinoma is a neuroendocrine tumor that secretes gastrin; the resultant hypergastrinemia causes gastric acid hypersecretion (Zollinger-Ellison syndrome). The chronic hypergastrinemia results in marked gastric acid hypersecretion and growth of the gastric mucosa with increased numbers of parietal cells and proliferation of gastric ECL cells. The gastric acid hypersecretion characteristically causes peptic ulcer disease, often refractory and severe, as well as diarrhea. The most common presenting symptoms are abdominal pain (70–100%), diarrhea (37–73%), and gastroesophageal reflux disease (GERD) (30–35%); 10–20% have diarrhea only. Although peptic ulcers may occur in unusual locations, most patients have a typical duodenal ulcer. Important observations that should suggest this diagnosis include peptic ulcer disease (PUD); with diarrhea; PUD in an unusual location or with multiple ulcers; PUD refractory to treatment or persistent; PUD associated with prominent gastric folds; PUD associated with findings suggestive of MEN 1 (endocrinopathy, family history of ulcer or endocrinopathy, nephrolithiases); and PUD without Helicobacter pylori present. H. pylori is present in >90% of idiopathic peptic ulcers but is present in <50% of patients with gastrinomas. Chronic unexplained diarrhea also should suggest gastrinoma.

Approximately 20–25% of patients with ZES have MEN 1, and in most cases hyperparathyroidism is present before the gastrinoma. These patients are treated differently from those without MEN 1; therefore, MEN 1 should be sought in all patients by family history and by measuring plasma ionized calcium and prolactin levels and plasma hormone levels (parathormone, growth hormone).

Most gastrinomas (50–70%) are present in the duodenum, followed by the pancreas (20–40%) and other intraabdominal sites (mesentery, lymph nodes, biliary tract, liver, stomach, ovary). Rarely, the tumor may involve extraabdominal sites. In MEN 1 the gastrinomas are also usually in the duodenum (70–90%), followed by the pancreas (10–30%), and are almost always multiple. About 60–90% of gastrinomas are malignant (Table 350-2) with metastatic spread to lymph nodes and liver. Distant metastases to bone occur in 12–30% of patients with liver metastases.

Diagnosis

The diagnosis of ZES requires the demonstration of inappropriate fasting hypergastrinemia, usually by demonstrating hypergastrinemia occurring with an increased basal gastric acid output (BAO) (hyperchlorhydria). More than 98% of patients with gastrinomas have fasting hypergastrinemia, although in 40–60% the level may be elevated less than tenfold. Therefore, when the diagnosis is suspected, a fasting gastrin should be determined first. It is important to remember that potent gastric acid suppressant drugs such as proton pump inhibitors (omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole) can suppress acid secretion sufficiently to cause hypergastrinemia; because of their prolonged duration of action, these drugs have to be discontinued for a week before the gastrin determination. Withdrawal of proton pump inhibitors (PPIs) should be performed carefully and is best done in consultation with GI units with experience in this area. The widespread use of PPIs can confound the diagnosis of ZES by raising a false-positive diagnosis by causing hypergastrinemia in a patient being treated with idiopathic peptic disease (without ZES) and lead to a false-negative diagnosis because at routine doses used to treat patients with idiopathic peptic disease, PPIs control symptoms in most ZES patients and thus mask the diagnosis. If ZES is suspected and the gastrin level is elevated, it is important to show that it is increased when gastric pH is 2.0(PH가 낮은데도 gastrin분비가 많아서 level이 높다) because physiologically hypergastrinemia secondary to achlorhydria (atrophic gastritis, pernicious anemia)(무산증에서는 산이 없으므로 feed back으로 가스트린분비 증가하므로 제외시켜야한다) is one of the most common causes of hypergastrinemia. Nearly all gastrinoma patients have a fasting pH 2 when off antisecretory drugs. If the fasting gastrin is >1000 pg/mL (increased tenfold 10배) and the pH is 2.0, which occurs in 40–60% of patients with gastrinoma(40~60%에서 가스트리노마가 있다), the diagnosis of ZES is established after the possibility of retained antrum syndrome has been ruled out by history. In patients with hypergastrinemia with fasting gastrins <1000 pg/mL and gastric pH 2.0, other conditions, such as (감별진단)H. pylori infections, antral G-cell hyperplasia/hyperfunction, gastric outlet obstruction, and, rarely, renal failure, can masquerade as ZES. To establish the diagnosis in this group, a determination of BAO and a secretin provocative test(세크레틴을 주면 gastrin 분비 증가) should be done. In patients with ZES without previous gastric acid–reducing surgery, the BAO is usually (>90%) elevated (i.e., >15 meq/h). The secretin provocative test is usually positive, with the criterion of a >120-pg/mL increase over the basal level having the highest sensitivity (94%) and specificity (100%).

Treatment: Gastrinomas

Gastric acid hypersecretion in patients with gastrinomas can be controlled in almost every case by oral gastric antisecretory drugs. Because of their long duration of action and potency, which allows dosing once or twice a day, the PPIs (H⁺,K⁺-ATPase inhibitors) are the drugs of choice. Histamine H₂-receptor antagonists are also effective, although more frequent dosing (q 4–8 h) and high doses are required. In patients with MEN 1 with hyperparathyroidism, correction of the hyperparathyroidism increases the sensitivity to gastric antisecretory drugs and decreases the basal acid output. Long-term treatment with PPIs (>15 years) has proved to be safe and effective, without development of tachyphylaxis. Although patients with ZES, especially those with MEN 1, more frequently develop gastric carcinoids, no data suggest that the long-term use of PPIs increases this risk in these patients. With long-term PPI use in ZES patients, vitamin B12 deficiency can develop; thus, vitamin B₁₂ levels should be assessed during follow-up.

With the increased ability to control acid hypersecretion, more than 50% of patients who are not cured (>60% of patients) will die from tumor-related causes. At presentation, careful imaging studies are essential to localize the extent of the tumor. A third of patients present with hepatic metastases, and in <15% of those patients the disease is limited, so that surgical resection may be possible. Surgical short-term cure is possible in 60% of all patients without MEN 1 or liver metastases (40% of all patients) and in 30% of patients long-term. In patients with MEN 1, long-term surgical cure is rare because the tumors are multiple, frequently with lymph node metastases. Therefore, all patients with gastrinomas without MEN 1 or a medical condition that limits life expectancy should undergo surgery by a surgeon experienced in the treatment of these disorders.