Zollinger-Ellison syndrome.

Zollinger-Ellison syndrome is caused by a gastrin-producing tumor, usually located in the pancreas or duodenal wall. The result is gastric hypersecretion and peptic ulcer. Diagnosis is made by measuring gastrin levels. Treatment for Zollinger-Ellison syndrome includes proton pump inhibitors and surgical removal of the tumor.

The disease, characterized by a triad of symptoms - gastric hypersecretion, recurrent therapy-resistant gastroduodenal ulcer and pancreatic non-insulin-producing tumor - was first described in 1955 by R. M. Zollinger and E. H. Ellison. Since then it has been called Zollinger-Ellison syndrome. A similar clinical picture is produced by hyperplasia of G-cells of the mucous membrane of the antrum of the stomach and gastrin-producing tumor of the pancreas (less often tumor of the stomach, duodenum). A tumor that produces gastrin is also called gastrinoma.

Zollinger-Ellison syndrome classification has not been developed. To determine treatment tactics, it is extremely important to divide gastrinomas into malignant and benign.

Epidemiology

In the USA, the incidence of Zollinger-Ellison syndrome is estimated at 0.1-1% among all patients with peptic ulcer. However, these data are also considered underestimated, since the characteristic clinical symptoms of peptic ulcer disease or NSAID-induced gastrointestinal lesions often prevent the clinician from performing a special examination of the patient to diagnose Zollinger-Ellison syndrome. Gastrinomas are usually detected at the age of 20-50 years, somewhat more often in men (1.5-2:1).

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Causes Zollinger-Ellison syndrome

Gastrinomas develop in the pancreas or duodenal wall in 80-90% of cases. In other cases, the tumor may be localized in the splenic hilum, intestinal mesentery, stomach, lymph node, or ovary. Approximately 50% of patients have multiple tumors. Gastrinomas are usually small (less than 1 cm in diameter) and grow slowly. Approximately 50% of them become malignant. About 40-60% of patients with gastrinomas have multiple endocrine neoplasia.

It has been established that gastrinoma cells have only a very limited ability to accumulate gastrin, and therefore the increasing overproduction of the hormone leads to the entry of an excess amount of it into the adjacent blood vessels. The tumor contains various molecular forms of gastrin, with the small one predominating - G-17 (about 70%), while in the blood of a patient with gastrinoma the large form of the peptide - G-34 prevails. Along with gastrin, in some cases tumor cells produce glucagon, insulin, PP.

Uncontrolled release of gastrin by tumor cells leads to gastric hypersecretion, which is caused by two interrelated mechanisms:

1. trophic effect of gastrin on the gastric mucosa, leading to its hyperplasia with an increase in the number of parietal cells;
2. increased stimulation of gastrin by hyperplastic mucous membrane.

Hypersecretion of hydrochloric acid by the stomach causes frequent (75%) development of gastroduodenal ulcers, often multiple, with a low tendency to scarring, a high tendency to recurrence and a high frequency of complications. Often ulcers are located in atypical zones (in a quarter of patients) - in the distal part of the esophagus, the postbulbar part of the duodenum and the upper part of the jejunum.

Along with other clinical manifestations of gastroduodenal ulcers, vomiting is characteristic, which occurs due to a significant increase in the volume of gastric juice and increased gastroesophageal reflux. Symptoms of Zollinger-Ellison syndrome are also diarrhea and steatorrhea. The load on the intestine with an increased volume of incoming gastric contents, non-physiological acidification of the intestinal contents lead to irritation and damage to the intestinal mucosa. Gastrin has a direct effect on the functional state of the intestine, inhibiting the absorption of water and electrolytes and stimulating its motility. All this leads to watery diarrhea. Steatorrhea is a consequence of irreversible inactivation of pancreatic lipase in a sharply acidic environment in the duodenal lumen. Along with this, precipitation of bile acids by hydrochloric acid and disruption of chylomicron formation occur.

Gastrinomas are usually located in the pancreas (40-80%), but can be located outside the gland, most often (15-40%) in the submucosa of the duodenum. Gastrinoma often (10-20%) occurs together with other hormone-active tumors. Unlike insulinoma, a gastrin-producing tumor is malignant in most cases (90%) and by the time it is recognized, it has already widely metastasized.

The size of gastrinomas located in the pancreas usually exceeds 1 cm, and tumors that develop in the wall of the duodenum are less than 1 cm in size. Very rarely, gastrinoma is detected in the hilum of the spleen, mesentery, stomach, liver, or ovary.

In 60% of cases, pancreatic tumors are malignant.

Multifocal tumor growth is observed in 60% of patients. In 30-50% of cases, gastrinomas have metastases by the time of diagnosis. Metastasis primarily occurs in the liver, bone metastases are also possible (primarily in the spine and sacrum), but they are always combined with metastases to the liver. When diagnosing, it should be taken into account that gastrinoma can occur as part of the syndrome of multiple endocrine neoplasia type I, inherited in an autosomal dominant manner, which is characterized by the presence of tumors in two or more endocrine glands. For multiple endocrine neoplasia type I, the most typical tumors are those of the anterior pituitary gland (from any cells), islet cells of the pancreas and parathyroid glands. In addition, carcinoid tumors (tumors originating from enterochromaffin cells), as well as adenomas of the adrenal glands and thyroid gland are possible. The probability that gastrinoma is caused by multiple endocrine neoplasia type 1 is 15-20%. Thus, the detection of gastrinoma dictates the need for a thorough study of the family history and a targeted search for tumors of other endocrine glands.

Symptoms Zollinger-Ellison syndrome

Zollinger-Ellison syndrome typically presents with an aggressive course of peptic ulcer disease, with ulcers developing in atypical locations (up to 25% distal to the duodenal bulb). However, in 25%, the diagnosis of ulcer is not established. Characteristic ulcer symptoms and complications (e.g., perforation, bleeding, stenosis) may develop. Diarrhea is one of the initial symptoms in 25-40% of patients.

The main symptoms of Zollinger-Ellison syndrome are abdominal pain similar to that of a peptic ulcer, as well as diarrhea and weight loss. In 25% of patients, the disease begins with gastrointestinal bleeding.

In 75% of cases, ulcers are located in the upper horizontal part of the duodenum, in 14% of cases - in its distal part and in 11% - in the jejunum.

Diarrhea develops in half of patients due to hypersecretion of hydrochloric acid and is accompanied by significant weight loss. Increased acidity leads to damage to the mucous membrane of the small intestine, inactivation of pancreatic lipase and precipitation of bile acids, which causes steatorrhea. High levels of gastrin lead to incomplete absorption of Na ⁺ and water, while intestinal peristalsis increases.

Diagnostics Zollinger-Ellison syndrome

Zollinger-Ellison syndrome may be suspected based on the history, especially if symptoms remain refractory to standard antiulcer therapy.

The most reliable test is serum gastrin levels. All patients have levels greater than 150 pg/mL; markedly elevated levels of greater than 1000 pg/mL in patients with appropriate clinical manifestations and increased gastric secretion greater than 15 mEq/hour are diagnostic. However, mild hypergastrinemia may occur in hypochlorhydric states (eg, pernicious anemia, chronic gastritis, use of proton pump inhibitors), in renal failure with decreased gastrin clearance, in extensive bowel resection, and in pheochromocytoma.

A secretin provocation test may be used in patients with gastrin levels less than 1000 pg/mL. Secretin solution is given intravenously at a dose of 2 mcg/kg with serial measurement of serum gastrin levels (10 and 1 minute before and 2.5, 10, 15, 20, and 30 minutes after administration). The characteristic response in gastrinoma is an increase in gastrin levels, in contrast to antral G-cell hyperplasia or typical peptic ulcer disease. Patients should also be tested for Helicobacter pylori infection, which commonly results in peptic ulcer disease and a modest increase in gastrin secretion.

When establishing a diagnosis, it is necessary to verify the tumor localization. The initial examination is abdominal CT or somatostatin receptor scintigraphy, which allows identifying the primary tumor and metastatic disease. Selective arteriography with image enhancement and subtraction is also effective. If there are no signs of metastasis and preliminary studies are questionable, endoscopic ultrasound is performed. An alternative is selective arterial secretin administration.

Workup plan for suspected Zollinger-Ellison syndrome

Since only a small proportion of patients with gastrointestinal ulcers have Zollinger-Ellison syndrome, this syndrome should be suspected only under certain conditions:

• Duodenal ulcers associated with diarrhea of unknown cause.
• Recurrent postoperative ulcers.
• Multiple ulcerations.
• Ulcers of the distal duodenum or jejunum.
• Family history of ulcerative lesions.

Further in-depth examination to diagnose Zollinger-Ellison syndrome is carried out only in the above-mentioned clinical situations.

The diagnosis of Zollinger-Ellison syndrome is established based on the study of the serum gastrin level. At the same time, a search is conducted for possible concomitant tumors within the framework of multiple endocrine neoplasia syndrome type I. The next step after establishing the diagnosis is to determine the specific localization of the tumor ( gastrinoma ) to assess the possibilities of its surgical removal.

The suspicion of Zollinger-Ellison syndrome is confirmed by the following factors.

1. Evidence of gastric hypersecretion (basal secretion of hydrochloric acid over 15 mmol/h in an intact stomach and over 5 mmol/h in a resected stomach; it is over 60% of the maximum acid secretion, since parietal cells are already stimulated by excess gastrin production in the basal state).
2. Evidence of the presence of fasting hypergastrinemia, despite hyperchlorhydria (exceeding the normal level of serum gastrin, equal to 30-120 pg/ml, by tens of times or more; an antiserum is used that includes all molecular forms of the peptide).
3. Establishing hypergastrinemia using a provocative secretin test (intravenous administration of secretin at a dose of 2 U/kg for 30 seconds, which usually causes inhibition of gastrin release, in gastrinoma leads to a paradoxical increase in its level in the blood - more than 100% of the basal level).

History and physical examination

The main symptoms of Zollinger-Ellison syndrome are abdominal pain, similar to the manifestations of peptic ulcer disease, as well as diarrhea and weight loss. In 25% of patients, the disease begins with gastrointestinal bleeding.

In 75% of cases, ulcers are located in the upper horizontal part of the duodenum, in 14% of cases - in its distal part and in 11% - in the jejunum.

Diarrhea develops in half of patients due to hypersecretion of hydrochloric acid and is accompanied by significant weight loss. Increased acidity leads to damage to the mucous membrane of the small intestine, inactivation of pancreatic lipase and precipitation of bile acids, which causes steatorrhea. High levels of gastrin lead to incomplete absorption of Na ⁺ and water, while intestinal peristalsis increases.

Laboratory research

Mandatory general clinical examination methods

• complete blood count;
• blood group determination;
• determination of the Rh factor;
• fecal occult blood test;
• general urine analysis.

Changes in the results of general clinical studies are not typical

Mandatory specialized laboratory tests

The concentration of gastrin in the blood serum is determined by the radioimmunological method if Zollinger-Ellison syndrome is suspected. The content of gastrin in the blood serum in this disease is increased and is 200-10,000 ng/l (the norm is less than 150 ng/l).

If basal gastrinemia of 200-250 ng/L is detected, provocative tests should be performed with intravenous calcium (5 mg/kg/h for 3 h) or secretin (3 U/kg/h). The test is positive if the serum gastrin content increases 2-3 times compared to the basal level (the sensitivity and specificity of this test for detecting gastrinoma is about 90%).

The combination of elevated blood gastrin levels and increased basal hydrochloric acid production makes the diagnosis highly probable. However, isolated detection of increased hydrochloric acid secretion is currently of only auxiliary importance for the diagnosis of Zollinger-Ellison syndrome. Fractional gastric secretion testing (detection of fasting hydrochloric acid hypersecretion of more than 15 mmol/h or 5 mmol/h after partial gastrectomy suggests the possibility of gastrinoma).

A non-specific marker of neuroendocrine tumors is chromogranin A. Its level of more than 10 nmol/l (the norm is less than 4.5 nmol/l) indicates the presence of multiple endocrine neoplasia. Its content of more than 75 nmol/l is observed in tumor metastases, which makes it necessary to assess the prognosis as unfavorable.

Radioimmunoassay and enzyme immunoassay of hormone concentrations in blood plasma (parathyroid hormone, insulin, prolactin, somatotropin, luteinizing and follicle-stimulating hormones ) are performed to exclude multiple endocrine neoplasia syndrome type I.

Additional examination methods

Determination of glucose concentration in the blood (detection of a possible combined tumor producing glucagon). Determination of calcium and phosphorus content in the blood and urine (detection of possible pathology of the parathyroid glands ).

Instrumental research

Mandatory examination methods

FEGDS or X-ray examination of the upper gastrointestinal tract. If ulcers are detected, FEGDS must be performed dynamically.

Ultrasound of the pancreas (detection of gastrinoma), liver (the most common localization of metastases), kidneys, adrenal glands, thyroid gland in order to identify the primary lesion, metastases, combined pathology of other endocrine glands. X-ray ( fluorography ) of the chest in order to identify metastases.

A special method for diagnosing endocrine tumors of the digestive organs and their metastases is scintigraphy with octreotide labeled with radioactive 111In, which has the highest sensitivity and specificity compared to other methods for determining the localization of gastrinoma. Octreotide administered intravenously is detected on somatostatin receptors after 24-48 hours and allows for visualization of the tumor during scintigraphy. Radioisotope octreotide can be used both for intraoperative detection of the tumor and its metastases and for assessing the radicality of the operation performed.

Additional examination methods

Endoscopic ultrasonography allows us to detect tumors in the head of the pancreas, the wall of the duodenum, and adjacent lymph nodes.

CT, magnetic resonance imaging (MRI), selective abdominal angiography, radiography, and radioisotope bone scanning are used to localize gastrinoma, rule out multiple endocrine neoplasia type I, and tumor metastases.

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Differential diagnosis

In the presence of a characteristic clinical picture of ulcerative gastrointestinal tract lesions in combination with the above clinical situations, differential diagnostic measures are carried out to confirm Zollinger-Ellison syndrome itself, as well as to identify its hereditary (within the framework of multiple endocrine neoplasia syndrome) or acquired nature. A special place in the differential diagnosis is occupied by clarification of the benign or malignant nature of the detected tumor.

Indications for consultation with other specialists

In any case, if Zollinger-Ellison syndrome is detected, consultations with an endocrinologist and surgeon are necessary.

Treatment Zollinger-Ellison syndrome

Treatment goals for Zollinger-Ellison syndrome:

• Reduction of clinical manifestations and prevention of complications caused by excessive autonomous secretion of gastrin by tumor cells.
• Prevention of tumor growth and its metastasis (if it is malignant).

Indications for hospitalization

Patients with suspected Zollinger-Ellison syndrome should be examined and treated in specialized gastroenterological or surgical hospitals. If the gastrinoma is localized, surgical removal of the tumor is indicated.

In benign gastrinoma with Zollinger-Ellison syndrome, uncomplicated gastroduodenal ulcers are treated conservatively. As a rule, longer treatment periods and higher doses of antisecretory drugs are required compared to peptic ulcer disease. In the absence of an effect from long-term treatment, as well as in gastroduodenal ulcers complicated by severe bleeding, in situations where tumorectomy is impossible (for example, the tumor localization is not established), it is necessary to decide on gastrectomy.

Non-drug treatment of Zollinger-Ellison syndrome

With an isolated tumor and surgical treatment, survival for 5-10 years is more than 90% versus 43 and 25%, respectively, with incomplete removal of the tumor.

Suppression of acid production

Proton pump inhibitors are the drugs of choice: omeprazole or esomeprazole orally 40 mg twice daily. The dose can be gradually reduced as symptoms resolve and acid production decreases. A maintenance dose is necessary; patients should take these drugs indefinitely unless undergoing surgical treatment.

Octreotide injections of 100-500 mcg subcutaneously 2-3 times a day also help reduce gastric secretion and may be an alternative treatment method if proton pump inhibitors are ineffective. A prolonged form of octreotide 20-30 mg intramuscularly once a month can be used.

Antisecretory drugs

Suppression of hydrochloric acid secretion is considered adequate when its values are less than 10 mmol/l before the next administration of the antisecretory drug, which determines the selection of the drug dose in each specific case.

Proton pump inhibitors ( rabeprazole, omeprazole, esomeprazole, lansoprazole) in ulcers associated with Zollinger-Ellison syndrome allow effective control of clinical manifestations. The use of drugs in this group, compared with the use of histamine H2-receptor blockers, _often leads to symptomatic improvement. H2-receptor blockers are used (cimetidine 1-3 g/day or more, ranitidine 600-900 mg/day, famotidine, etc.). The dose is determined individually by analyzing gastric secretion. In some patients, symptoms are quickly eliminated. If the effect is partial, H2-receptor blockers are prescribed in combination with anticholinergic drugs, mainly gastrozepine. An effective agent is a blocker of hydrochloric acid production (an "acid pump" blocker) omeprazole (90 mg/day). The effectiveness of selective proximal vagotomy does not exceed the effectiveness of H2-receptor blockers.

If oral administration of drugs is not possible, for example during chemotherapy or in the preoperative period, parenteral administration of proton pump inhibitors ( pantoprazole, omeprazole) is possible. High doses of histamine H2-receptor blockers (ranitidine, famotidine) can be used _, but they are less effective than proton pump inhibitors.

Purely conservative treatment has a relatively favorable prognosis: almost 90% of patients continue to live for 5 years or more.

• Octreotide

The somatostatin analogue octreotide can be used not only for the diagnosis of gastrinoma, but also for the treatment of Zollinger-Ellison syndrome.

Octreotide is recommended to be administered at a dose of 0.05-0.2 mg 2-3 times a day intramuscularly. Positive changes in clinical manifestations and laboratory parameters are observed in 50% of patients.

In the case of a malignant tumor with metastases, octreotide stabilizes clinical symptoms and slows down the progression of the process.

Surgical treatment

Surgical removal is indicated in patients without obvious signs of metastasis. During surgery, duodenotomy and endoscopic transillumination or intraoperative ultrasound allow localization of the tumor. Surgical treatment is possible in 20% of patients if the gastrinoma is not part of multiple endocrine neoplastic syndrome.

Surgical treatment is the method of choice. Three methods of surgical treatment are used: removal of the gastrinoma itself, resection of the pancreas and gastrectomy.

Radical resection of localized gastrinoma not associated with multiple endocrine neoplasia and Zollinger-Ellison syndrome, in the absence of metastases, is the most favorable treatment method from a prognostic point of view. Difficulties in determining the tumor localization complicate such treatment. Nevertheless, with an optimal combination of preoperative examination (CT, MRI, angiography, endoscopic ultrasound, octreotide scintigraphy, etc.) and the use of special techniques directly during the intervention (including intraoperative scintigraphy), the possibility of detecting gastrinoma is more than 90%. It should be emphasized that if possible malignancy of one or more gastrinomas is suspected, surgical intervention is indicated, the extent of which is difficult to predict before the operation.

If there is confidence in the precise mapping of the primary lesions, tumorectomy or pancreatic resection is indicated depending on the degree of tumor malignancy. Only if it is impossible to detect the tumor localization, there is no effect from long-term treatment and gastroduodenal ulcers complicated by severe bleeding, the question of gastrectomy is raised.

Surgical treatment in the presence of liver metastases has a positive effect in terms of reducing symptoms caused by hypersecretion of gastrin, and in some patients leads to an increase in life expectancy.

As a palliative measure for liver metastases, selective embolization of the hepatic artery or selective infusion of chemotherapeutic agents into the hepatic artery can be performed.

Chemotherapy

In patients with metastatic disease, the preferred chemotherapy for islet cell tumors is streptozotocin in combination with 5-fluorouracil or doxorubicin. This treatment can shrink tumors (50-60%), reduce gastrin levels, and is an effective adjunct to omeprazole. Unfortunately, chemotherapy does not cure patients with metastatic disease.

The possibilities of chemotherapy in the treatment of patients with malignant neuroendocrine tumors are very limited.

Mono- and polychemotherapy can be performed only in cases of rapid tumor growth and low degree of its differentiation, in the metastatic form of the disease and in those patients who are not considered candidates for surgery. The following drugs are recommended for chemotherapy.

• Streptozocin 0.5-1.0 g/m2 ^daily for 5 days with a repeat course after 6 weeks.
• Doxorubicin intravenously at 250 mg/m2 ^per day for 5 days with an interval of 1 month.

The effectiveness of these two drugs is low. Chlorozotocin and 5-fluorouracil are also used. The positive effect of chemotherapy for 5 months is observed in no more than 17% of patients.

Mode

Depends on the chosen tactics of patient management. In case of conservative treatment of ulcerative lesions of the gastrointestinal tract against the background of benign gastrinoma, the regimen is similar to that for peptic ulcer disease.

Diet

It also depends on the chosen tactics of patient management. In case of conservative treatment of ulcerative lesions of the gastrointestinal tract against the background of benign gastrinoma, the diet is similar to that for peptic ulcer disease.

Further management of the patient

The measures depend on the chosen treatment tactics.

Patient education

The patient should be informed about the need to follow the doctor's recommendations, including those related to lifestyle changes, diet, and taking antisecretory drugs. If surgical treatment is necessary, a conversation should be held with the patient to explain the appropriateness of the intervention.

Screening

Screening for Zollinger-Ellison syndrome is not performed. If the patient has atypical ulcerative gastrointestinal tract lesions and standard doses of antisecretory drugs are ineffective, the need for a special examination of the patient for the diagnosis of Zollinger-Ellison syndrome should be assessed.

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Prevention

Primary prevention measures have not been developed. Secondary prevention consists of timely and adequate diagnostics and treatment.

Forecast

Before the advent of drugs that suppress gastric secretion, the mortality rate from complications of ulcers caused by Zollinger-Ellison syndrome was very high, and gastrectomy was the only method that allowed to prevent the development of fatal complications. At present, fatal outcomes are also caused by severe complications of ulcerative lesions of the gastrointestinal tract. But the size of the primary tumor and metastasis are of decisive importance for the prognosis. Thus, in patients with localized gastrinoma or with metastases only to the nearest lymph nodes without metastases to the liver, the five-year survival rate with adequate treatment can reach 90%. In patients with metastases to the liver, the five-year survival rate is 20-30%.