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Zollinger Ellison syndrome pancreatic gastrinoma. Zollinger-Ellison syndrome: causes, clinical picture, treatment


For quotation: Okhlobystin A.V. DIAGNOSIS AND TREATMENT OF ZOLLINGER-ELLISON SYNDROME // Breast cancer. 1998. No. 7. S. 4

Zollinger-Ellison syndrome (ZES) is a clinical manifestation of hypergastrinemia caused by a gastrin-producing tumor of the pancreas or duodenum. This disease must be excluded in patients with hard-to-scar, often recurrent ulcers, especially after surgical treatment of peptic ulcer in patients with esophagitis, diarrhea, and weight loss. ZES may be a component of multiple endocrine adenomatosis type 1. Complete removal of gastrinoma is impossible in 70 - 70% of patients, which requires massive continuous antisecretory therapy under the control of endoscopy and the level of gastric secretion.

The Zollinger-Ellison syndrome (ZES) is a clinical manifestation of hypergastrinemia caused by a gastrin-producing tumor of the pancreas or duodenum. This disease should be excluded in patients with uncicatrizing, frequently recurrent ulcers particularly after surgery for ulcer diseases in patients with esophagitis, diarrhea, weight loss. ZES may be a component of multiple endocrine adenomatosis type I. Gastrinoma cannot be completely removed in 70-70% of patients as major continuous antisecretory therapy should be performed by monitoring under guidance of endoscopy and by controlling the level of gastric secretion.

A.V. Okhlobystin, Department of Propaedeutics of Internal Diseases, 1st year. Faculty of MMA named after. THEM. Sechenov (Head - Academician of the Russian Academy of Medical Sciences Prof. V.T. Ivashkin)

A.V.Okhlobystin, Department of Internal Propedeutics, (Head - Prof. V.I.Ivashkin, Academician of the Russian Academy of Medical Sciences), First Therapeutical Faculty, I.M.Sechenov Moscow Medical Academy

IN 1955 R.M. Zollinger and E.H. Ellison described a syndrome characterized by severe hypergastrinemia, gastric hypersecretion, and peptic ulcers of the upper gastrointestinal tract. Hypergastrinemia in this disease is associated with the presence of a hormonally active tumor - gastrinoma.
According to statistics, the prevalence of Zollinger-Ellison syndrome (ZES) ranges from 0.1 to 4 per 1 million population, but the actual incidence of the disease is much higher, which is associated with the significant complexity of diagnosis. It is known that the correct diagnosis is established for patients on average 5 to 7 years from the onset of the first symptoms. Patients with SZE account for up to 1% of all patients with duodenal ulcers.

Pathogenesis

Normally, the regulation of gastrin secretion is carried out through a negative feedback mechanism: the release of hydrochloric acid inhibits the work of G-cells in the antrum of the stomach, which secrete gastrin. However, hydrochloric acid does not affect the production of gastrin by the tumor, which leads to uncontrolled hypergastrinemia.
The occurrence of gastrointestinal ulcers in SZE is not associated with Helicobacter infection r pylori. The incidence of this infection in patients with gastrinomas is 23% (10% with active infection), which is significantly lower compared to the general population and patients with peptic ulcers.
Gastrinomas are classified as APUD cell adenomas (Kulchitsky cells). Typically, tumors form and secrete not only gastrin, but also other hormones: pancreatic polypeptide, somatostatin, adrenocorticotropic hormone, glucagon, insulin, vasoactive intestinal peptide (VIP), but most often the effect of these substances is not clinically manifested. Tumors can be single or, more often, multiple, ranging in size from 2 to 20 mm. In the vast majority of patients (about 80%), the tumors are located in the so-called “gastrinoma triangle”, which is formed by the pancreas (body and tail), duodenum and the junction of the cystic and common hepatic duct. Traditionally, GES has been described as an endocrine tumor of the pancreas, but about a third of gastrinomas are located in the duodenal wall or peripancreatic lymph nodes. In addition, tumors can be localized in the hilum of the spleen and the wall of the stomach.
Table 1. Provocative tests to detect SES

Disease Serum gastrin levels during challenge tests

secretin

calcium

std. breakfast

GES (gastrinoma) - > 200 pg/ml) --- (> 395 pg/ml) = or - (up to 50%)
Ulcer

Duodenum
G cell hyperplasia
Note: Ї - decrease; » - no change, slight increase or decrease; - - slight increase; -- - moderate increase; --- - sharp increase.

Gastrinomas can be malignant in 2/3 of cases, but their histological heterogeneity often makes differentiation between malignant and benign tumors difficult. Tumors may appear similar to carcinoids on light microscopy, especially if they arise from the small intestine or stomach. Malignant gastrinomas usually grow slowly. Metastasis occurs in regional lymph nodes, liver, as well as in the peritoneum, spleen, bones, skin, and mediastinum.
Scheme 1. Diagnosis of multiple endocrine adenomatosis type 1.

1. Tumors or hyperplasia, usually multiple, of various endocrine organs:
. Parathyroid glands (hyperplasia) - 87 - 97% of cases: hypercalcemia, nephrolithiasis.
. Pancreas - 80%, usually functional islet cell tumors
(gastrinoma - 54%, insulinoma - 21%, glucagonoma - 3%, VIPoma - 1%).
. Pituitary gland - 6 5%, usually non-functioning tumors: prolactin hypersecretion, visual compression
nerves, acromegaly (hypersecretion of growth hormone) - 1%, Cushing's syndrome (hypersecretion of ACTH) - 1%.
. Adrenal cortex - 38%, usually non-functioning tumors.
. Thyroid gland - 19%, usually non-functioning tumors.
2. Inherited in an autosomal dominant manner (defect of chromosome 11), high penetrance.
Family history is complicated in 50 - 75% of cases.
3. Age over 20 years, usually 40 - 50 years.

Approximately 80% of patients with ZES have isolated (sporadic) gastrinomas. In 20% of patients, gastrinomas are a component of multiple endocrine adenomatosis type 1 (Wermer syndrome, MEN-1). In addition to gastrinoma, most of these patients have hyperplasia of the parathyroid glands and increased serum calcium levels. In addition, multiple endocrine adenomatosis can manifest itself as tumors or hyperplasia of pancreatic islet cells (b-cell adenoma, glucagonoma, VIPoma) , adrenal cortex, pituitary gland and thyroid gland (Scheme 1). In 47% of cases, the tumors are malignant, most often metastasizing to the liver.

Clinical picture

The most important sign of gastrinoma, which is observed in 90 - 95% of patients, is the appearance of ulcers of the gastrointestinal tract. In approximately 75% of patients, ulcers occur in the proximal duodenum and stomach. Ulcers can be localized in the distal parts of the duodenum, jejunum (up to 25% of cases). Usually the ulcers are single, but can be multiple, especially in postbulbar localization. The clinical symptoms of ulcers that occur with gastrinoma resemble those of a common peptic ulcer, however, SZE is characterized by persistent abdominal pain that is difficult to respond to conventional antiulcer therapy. Ulcers often recur, complications develop: bleeding, perforation, stenosis. Complications of ulcers are severe and are the main cause of death in patients. About half of patients experience esophagitis.
Scheme 2. Situations in which the presence of a PPA should be excluded.

A characteristic symptom of this disease is diarrhea, which occurs in 30 - 65% of patients. Moreover, in 25–40% of patients, diarrhea is the first symptom, and in 7–18% it is the only symptom. Severe hypersecretion of hydrochloric acid leads to damage to the mucous membrane of the jejunum, which causes increased motility of the small intestine, increased secretion of potassium ions and slower absorption of sodium and water. At a low pH value, inactivation of pancreatic enzymes (in particular lipase) and precipitation of bile salts occurs with impaired formation of micelles. As a result, the absorption of fats and monoglycerides decreases, steatorrhea and weight loss occur.
Scheme 3. Management tactics for patients with SES

. Localization of the tumor has been established: surgical treatment (during surgery and in the postoperative period carry out intravenous administration of H2-blockers); re-examination for gastrinoma
(gastric secretion, serum gastrin) are carried out 1, 6 and 12 months after surgery, then every 1 - 2 years for 3 - 5 years.
. The localization of the tumor has not been established: maintenance therapy with proton inhibitors pumps; repeat examination (EGD, gastric secretion, serum gastrin) is carried out every 6 - 12 months.
. Multiple endocrine adenomatosis type 1: maintenance therapy with inhibitors
proton pump; re-examination (EGD, gastric secretion, endocrinological examination, including hormone testing) is carried out every 6 to 12 months.
. Gastrinoma with metastases: maintenance therapy with proton pump inhibitors;
observation by an oncologist. Treatment is usually ineffective.

Metastases to regional lymph nodes develop in 1/3 of patients with ZES. In 10 - 20% of patients, gastrinoma metastases to the liver are detected at the initial treatment, and metastasis subsequently occurs to the bones. The presence of liver metastases usually determines a poor prognosis for the patient, but Ellison also described several patients with liver metastases who lived 15 to 20 years after total gastrectomy. In patients after successful tumor resection or if the tumor was not found during surgery, the 10-year survival rate is 60 - 100%. For unresectable tumors, the 5-year survival rate is 40%. The survival rate of patients with multiple endocrine adenomatosis type 1 is usually higher than that of patients with isolated EDS. This is associated with more pronounced clinical symptoms, which leads to earlier diagnosis and initiation of antisecretory therapy.

Diagnostics

SES should be suspected in all patients with severe esophagitis (Savary-Miller grade 3 - 4), especially in those who suffer from intractable duodenal ulcers or diarrhea of ​​unknown origin (Scheme 2). The presence of SZE in gastric ulcers is unlikely: such ulcers are observed in less than 5% of patients with gastrinomas.
An aspiration study of gastric secretion is of great importance for diagnosis: in patients with SZE, the basal production of hydrochloric acid in 1 hour (BAO) is 15 mEq/h or more. Sometimes BAO exceeds 100 mEq/h. After surgery for a gastric or duodenal ulcer, a BAO level > 5 mEq/h is diagnostic. A BAO value of more than 15 mEq/h occurs in only 10% patients suffering from peptic ulcer, while with SZE - in 70% of patients. Another characteristic feature is that with SZE, the basal production of hydrochloric acid is 60% or more of the maximum (MAO). It should be remembered, however, that both high acid production and a small gap between the basal and maximum production of hydrochloric acid can be observed in patients with peptic ulcer and healthy individuals.
With SZE, the level of serum gastrin is increased: in 70% of patients it exceeds 100 pg/ml when determined on an empty stomach by radioisotope method and can reach 450,000 pg/ml. However, an increase in the level of serum gastrin can be observed in diseases such as pernicious anemia , chronic atrophic gastritis, pheochromacetoma, renal failure, after extensive resection of the small intestine Sometimes (in less than 1% of cases) with duodenal ulcer, hypergastrinemia may be observed due to hyperfunction and/or hyperplasia of G-cells of the antrum. In this case, a biopsy reveals an increase in gastrin content in the mucous membrane of the antrum. A gastrin level of more than 250 pg/ml is considered diagnostically significant for SZE, and more than 1000 g/ml is considered unconditionally significant.
In cases where high gastric secretion is observed but serum gastrin levels are between 100 and 1000 pg/ml, the diagnosis of gastrinoma should be confirmed using provocative tests. Tests are performed with secretin, calcium or a standard breakfast. When conducting a test with secretin, Kabi-secretin is injected intravenously at a dose of 2 units/kg/hour; gastrin levels are measured twice before the injection and after it every 5 minutes for 30 minutes (another option: at 2, 5, 10, 15 and 20 minutes after the injection). The calcium test is carried out as follows: a 10% solution of calcium gluconate is administered intravenously for 3 hours at a dose of 5 mg Ca/kg/h; gastrin is determined before the administration of calcium and every 30 minutes for 4 hours. A test with calcium is more dangerous for the patient compared to a test with the introduction of secretin, so it is not recommended as a primary test. When conducting a test with a standard breakfast, gastrin activity is determined on an empty stomach and every 15 minutes for 1.5 hours after meals.
SZE is characterized by a sharp increase in gastrin content after the administration of a calcium solution, a paradoxical increase after the injection of secretin, and after a test breakfast there is no increase in gastrin by more than 50% (Table 1). The secretin test has the greatest diagnostic value. It is positive in 87% of patients with ZES. The indication for a calcium test is a negative result of the secretin test (13% of patients with ZES). Unfortunately, a calcium test can additionally identify only 4% of patients with gastrinomas. Thus, in 9% of patients with SES, both provocative tests are negative.
To choose the right treatment tactics, it is fundamentally important to determine whether the gastrinoma is isolated or whether it exists as part of multiple endocrine adenomatosis type 1 (see Diagram 1). In the latter case, most patients have a family history; hyperparathyroidism occurs first, and only then gastrinoma. However, patients have been described in whom signs of hyperparathyroidism appeared years after the development of a full-blown clinical picture of ZES. A study of the spectrum of hormones, radiography of the sella turcica, and computed tomography of the pituitary gland will help establish the diagnosis.
No less difficult than the laboratory diagnosis of gastrinoma is establishing its location. This is due to the small size of gastrinomas. A tumor less than 1 mm in size can be malignant and metastasize to regional lymph nodes and liver. It is usually difficult to detect a tumor smaller than 1 cm. The algorithm for examining a patient to identify the location of gastrinoma includes:
. ultrasound examination of the abdominal organs;
. computed tomography of the abdominal cavity;
. angiography of the liver/pancreas.
In addition, endoscopic Ultrasound examination, transillumination during diagnostic laparotomy and intraoperative ultrasound can detect 80% of tumors measuring 1 cm or more located in the gastrinoma triangle. Skeletal scanning makes it possible to detect bone metastases.

Treatment of patients with SZE

For isolated gastrinomas of established localization, tumor resection is performed. This turns out to be possible in 20% of patients with isolated gastrinomas. The main indications for surgical treatment are: established tumor localization, absence of multiple endocrine adenomatosis type 1, metastases. However, even in such patients after tumor resection, remission within 5 years is observed in less than 30% of cases. Therefore, for most patients with ZES, symptomatic treatment is necessary: ​​relief of the symptoms of the disease and achieving scarring of duodenal and jejunal ulcers using antisecretory therapy.
In patients after partial gastrectomy or vagotomy, a more severe course of SZE is observed. According to Zollinger, the worst operation for SZE is partial gastrectomy. After such operations, even more active antisecretory therapy is necessary.
Powerful continuous antisecretory Therapy under constant monitoring using endoscopy and gastric secretion studies is the main component of the conservative treatment of patients with ZES. For this purpose, two groups of drugs are used: H blockers 2 -histamine receptors and proton pump inhibitors. Before the advent of these drugs, the only option to suppress gastric secretion was to perform a total gastrectomy.
H blockers 2 -receptors should be prescribed at a dose 2 to 5 times higher than for duodenal ulcer. In particular, ranitidine is used in a dose of 1.5 - 9 g/day. The drugs must be taken more often: every 4 - 6 hours. According to the recommendations of the National Institutes of Health (USA), the goal of therapy is H 2-blockers are aimed at reducing BAO to less than 10 mEq/h. Unfortunately, with the help of H 2 blockers, even at a high dose, it can be difficult to achieve this indicator (which may not be sufficient to scar ulcers and subside esophagitis). In addition, in most cases, an annual dose increase is necessary. Therefore, currently H2 blockers -receptors are used only for intravenous administration during surgical interventions, in the postoperative period and when it is impossible to take oral medications.
Proton pump inhibitors (omeprazole and lansoprazole), which block the final stage of hydrochloric acid secretion, have a more powerful and long-lasting antisecretory effect compared to H 2 -blockers. With these drugs, BAO can be easily reduced to 10 mEq/h, and levels of no more than 2 mEq/h can usually be achieved. The use of proton pump inhibitors does not require an increase in the daily dose over time; moreover, the dose can often be slightly reduced.
Omeprazole and lansoprazole have approximately equal efficiency. Lansoprazole, however, has a greater number of binding sites in the parietal cell, which explains its slightly higher activity under experimental conditions. Clinical studies using 24-hour pH-metry showed that omeprazole (at a dose of 20 - 160 mg/day) and lansoprazole (at a dose of 30 - 165 mg/day) in patients with SZE have a similar pH profile and average pH level during the day (respectively 1.8 - 6.4 units and 2.1 - 6.4 units). Despite existing publications that the daily dose of proton pump inhibitors can be prescribed in one dose, dividing it into two doses increases the effectiveness of therapy.
Patients with SZE require careful selection and monitoring of therapy. The goal of therapy in non-operated patients with uncomplicated SES is to reduce BAO below 5 mEq/h. Patients with esophagitis or after gastric surgery (except total gastrectomy) require more pronounced suppression of gastric acid production (up to BAO less than 1 mEq/h). The initial dose is 60 mg/day of omeprazole or lansoprazole. Then, “titration” is carried out with the drug: the daily dose is increased every 1 - 2 weeks by 20 - 30 mg under the control of gastric secretion studies until the required BAO level is achieved. A study of gastric secretion is carried out approximately 1 hour before taking the next dose of the drug. To assess the adequate frequency of dosing, it is advisable to perform 24-hour pH measurements. Subsequent follow-up examinations, including endoscopy and gastric intubation, are carried out after 3 months. The absence of recurrence of ulcers during this period may indicate a potentially resectable tumor. Dynamic observation of patients (clinical examination, endoscopic gastroduodenoscopy, gastric intubation) is carried out 2-4 times during the first year, then 2 times a year. If BAO is zero and MAO is below 5 mEq/h, a careful dose reduction is possible, but if MAO is equal to or more than 5 mEq/h, the dose of the drug should be left the same.
Failure to comply with the prescribed therapy regimen or regular follow-up examination is an indication for total gastrectomy. Patients with ZES usually tolerate this operation well, but in the future they need intramuscular administration of vitamin B12, iron, and calcium.
Even with careful clinical monitoring, the course of ZES is unpredictable and difficult to control with antisecretory drugs. There are known cases of perforation of ulcers and bleeding after total gastrectomy in patients with acid production less than 1 mEq/h. Systematic endoscopy can prevent such situations.
For gastrinoma with metastases, in addition to antisecretory therapy or total gastrectomy, the administration of streptozocin and 5-fluorouracil can reduce the size of the tumor and reduce the level of serum gastrin.
The presence of multiple endocrine adenomatosis type 1 requires first of all the removal of the parathyroid glands. In some patients after this The operation normalizes the level of gastrin and gastric secretion.
Thus, surgical treatment cannot be performed in most patients with ZES. These patients require ongoing therapy with proton pump inhibitors under endoscopic control and gastric secretion studies.

Literature:

1. Guide to gastroenterology: in three volumes / Under the general editorship of F.I. Komarov and A.L. Grebeneva. T.1 Diseases of the esophagus and stomach / F.I. Komarov, A.L. Grebenev, A.A. Sheptulin et al. - M.: Medicine, 1995. - P. 672: ill.
2. Hirschowitz B.I. Zollinger-Ellison syndrome: pathogenesis, diagnosis, and management. Amer. J. Gastroent. 1997; 92(3):44-8.
3. Weber H.C., Venzon D.J., Jensen R.T., Metz DC. Studies on the interrelation between Zollinger - Ellison syndrome, Helicobacter pylori, and proton pump inhibitor therapy. Gastroent. 1997; 112(1):84-91.
4. Hirschowitz B.I. Pathobiology and management of hypergastrinemia and the Zollinger-Ellison syndrome. Yale J Biol Med 1992; 65:659-76.
5. Jensen R.T., Gardner J.D. Zollinger-Ellison syndrome: Clinical presentation, pathology, diagnosis and treatment. In: Zakim D, Dannenberg AJ, eds. Peptic ulcer disease and other acid-related disorders. New York: Academic Research Assoc Inc 1991:117-212.
6. Schroder W., Holscher A.H., Beckurts T., et al. Duodenal microgastrinomas associated with Zollinger - Ellison syndrome. Hepato-Gastroent. 1996; 43(12):1465-9.
7. Mignon M., Ruszniewski R., Haffar S., et al. Current approach to the management of tumoral process in patients with gastrinoma. World J Surg 1986; 10:703-10.
8. Norton J.A., Doppman J.L., Jensen R.T. Curative resection in patients with Zollinger - Ellison syndrome: Results of a 10 year prospective study. Am Surg 1992; 215:8-18.
9. Farley D.R., van Heerden J., Grant C.S., et al. The Zollinger - Ellison syndrome: A collective surgical experience. Ann Surg 1991; 215:561-9.
10. Internal diseases. In 10 books. Book 7: trans. from English / Ed. E. Braunwald, K.J. Isselbacher, R.G. Petersdorf and others - M.: Medicine, 1996. - P. 720: ill.
11. Jensen R.T., Maton P.N. Zollinger-Ellison syndrome. In: Gustavsson S., Kumar D., Graham D.Y., eds. The stomach. London: Churchill Living stone, 1991:341-74.
12. Metz D.C., Pisegna J.R., Ringham G.L., et al. Prospective study of the efficacy and safety of lansoprazole in Zollinger-Ellison syndrome. Dig Dis Sci 1993; 38:245-56.
13. Metz D.C., Pisegna J.R., Fishbeyn V.A., et al. Currently used doses of omeprazole in the management of gastric acid hypersecretion in Zollinger - Ellison syndrome are too high. Gastroenterology 1992; 103:1498–1508.
14. Jensen R. T., Metz D. C., Koviack P. D., et al. Prospective study of the long-term efficacy and safety of lansoprazole in patients with the Zollinger-Ellison syndrome. Aliment Pharmacol Ther 1993; 7:41-50.
15. Nagaya H., Satoh H., Maki Y. Possible mechanism for the inhibition of acid formation by the proton pump inhibitor AG 1749 in isolated canine parietal cells. J Pharmacol Exp Ther 1990; 252:1289-95.
16. Tolman K.G., Sanders S.W., Buchi K.N. Gastric pH levels after 15 mg and 30 mg of lansoprazole and 20 mg omeprazole. Gastroenterology 1994; 106:A172.
17. Ramdani A., Paul G., Ruszniewsji Ph., et al. Comparative effectiveness of lansoprazole and omeprazole on 24-hour intragastric pH measurement in 9 cases of Zollinger - Ellison syndrome. Gastroenterology 1992; 102:A151.
18. Maton P.N., Frucht H., Vinayek R., et al. Medical management of patients with Zollinger-Ellison syndrome who had previous gastric surgery: A prospective study. Gastroenterology 1988; 94:294-9.
19. Hirschowitz B.I. Clinical course of nonsurgically treated Zollinger-Ellison syndrome. In: Mignon M, Jensen RT, eds. Endocrine tumors of the pancreas, vol. 23. Basel, Switzerland: S. Karger AG, 1995:360-71. Frontiers in Gastrointestinal Research series.
20. Miller L.S., Vinayek R., Frucht H., et al. Reflux esophagitis in patients with Zollinger - Ellison syndrome. Gastroenterology 1990; 98:341-6.
21. Berkow R. ed.-in-chief, Fletcher A.J.: The Merck manual of diagnosis and therapy. Merck research laboratories. 16th ed. Rahway, NJ, 1992.


FAST NAVIGATION - Zollinger-Ellison Syndrome

What is Zollinger-Ellison syndrome?

Zollinger-Ellison syndrome (gastrinoma) belongs to the group of acid-dependent diseases of the gastrointestinal tract. Occurs due to a tumor of the head or tail of the pancreas. The neoplasm intensively produces gastrin, which stimulates the production of hydrochloric acid.

Gastrinomas are hormonally active tumors.

As a rule, single tumors occur, but there are cases of multiple endocrine neoplasia (MEN syndrome). In rare cases, gastrinoma may be located in the wall of the stomach.

Reasons

To date, the etiological factors of the disease are unknown. It is believed that if Zollinger-Ellison syndrome is part of the MEN syndrome, its etiology is associated with genetic disorders. In particular, a defect in the gene of the 11th chromosome causes the appearance of MEN-1 syndrome (Wermer syndrome), which is manifested by malignant neoplasms of the parathyroid glands, pancreas (gastrinoma) and the anterior lobe of the pituitary gland (adenohypophysis).

In cases of Zollinger-Ellison syndrome, the production of large amounts of gastrin causes hypersecretion of hydrochloric acid, which results in the appearance of multiple ulcers on the mucous membrane of the stomach and duodenum.

Clinical picture

The clinical picture of the disease is similar to the symptoms of gastric and duodenal ulcers. Therefore, Zollinger-Ellison syndrome is very often confused with other acid-related diseases of the digestive tract (gastritis, peptic ulcers, GERD). However, treatment of this disease with conventional acid-reducing drugs does not bring relief to the patient.

The most typical symptoms of Zollinger-Ellison syndrome are:

  • Pain in the epigastric region. Pain is associated with eating: if the ulcers are in the upper parts of the stomach (cardiac part and body of the stomach), the pain goes away within half an hour after eating. In cases of ulcers localized in the pyloric part of the stomach, the pain disappears after 40-60 minutes. If the ulcers are in the duodenum, the patient is characterized by hunger pain and night pain. However, this division is rather arbitrary, since in most cases the ulcers are located diffusely in the stomach and duodenum. Ulcers of the initial sections of the jejunum are less common.
  • Frequent diarrhea is associated with the entry of acidic contents into the intestines. In patients with Zollinger-Ellison syndrome, the acidity of gastric juice is so increased that the compensatory mechanisms of the duodenum do not work fully and the acidic contents are evacuated further through the intestine. This leads to increased motor-evacuation function of the digestive tract and, as a result, to diarrhea.
  • Weight loss, which occurs due to constant diarrhea.
  • Constant heartburn.
  • Pain behind the sternum - appears as a result of reflux of stomach contents into the esophagus.
  • Nausea and vomiting.
  • Belching and sour taste in the mouth.
  • Bad breath.
  • Gastrointestinal bleeding.
  • With prolonged illness, malignant liver tumors may occur.

Diagnostics

A specialist may suspect a correct diagnosis if the disease lasts for a long time without significant improvement due to the action of medications. Gastroenterologists carefully collect complaints and medical history from patients.

During a general examination, the specialist pays attention to the patient’s tongue coated with a white coating, severe pain on palpation in the epigastrium, and in some cases an increase in the lower border of the liver is observed.

After a detailed examination, the patient is prescribed the necessary laboratory and instrumental tests:

  • Complete blood count – with severe disease activity, a decrease in hemoglobin and red blood cells may be observed
  • Biochemical blood test to determine the level and fractions of bilirubin. In some cases, patients experience jaundice.
  • Blood electrolytes. Especially the level of calcium in the blood. This is necessary to exclude MEN syndrome with pathology of the parathyroid glands.
  • Determination of levels of parathyroid hormone, somatotropin, prolactin. If the levels of these hormones increase, specialists must exclude MEN syndromes in the patient.
  • Determination of gastrin level in the blood. In patients with Zollinger-Ellison syndrome, there is an increase in gastrin in the blood of more than 1000 pg/ml.
  • Secretin test. In cases of increased gastrin more than 150 pg/ml, but not higher than 1000 pg/ml, a special secretin test is performed. The essence of the method is the intravenous administration of 2 units/kg of secretin, which increases gastrin levels in all patients with Zollinger-Ellison syndrome by more than 200 pg/ml.
  • pH-metry with determination of the level of hydrochloric acid secretion. In all patients, the basal secretion of hydrochloric acid exceeds acceptable levels (15 mEq/h).
  • Fibrogastroduodenoscopy allows you to identify defects in the mucous membrane of the stomach and duodenum, conduct their biopsy, followed by histological examination.
  • Ultrasound of the abdominal organs. A necessary diagnostic method with which one can detect concomitant diseases of the abdominal organs, as well as malignant liver damage.
  • CT, MRI - allow you to detect the exact localization of gastrinoma.
  • Scintigraphy with In-labeled octreotide. This diagnostic method is based on identifying specific somatostatin receptors in tissues. Most neuroendocrinological tumors (including gastrinoma) have a large number of such receptors.
  • Endosonography is a method of visualizing gastrinoma in the head of the pancreas and in the wall of the duodenum.
  • Consultation with an endocrinologist, oncologist.

Israeli and German clinics use all the necessary methods for diagnosing Zollinger-Ellison syndrome.

Foreign specialists successfully carry out differential diagnosis between gastrinoma and other acid-related diseases of the gastrointestinal tract.

Treatment of Zollinger-Ellison syndrome abroad

The most effective treatment for this disease is surgical removal of the tumor. However, in some cases the localization of gastrinoma is very difficult to detect. This is due to the fact that the neoplasm is very small in size. Israeli and German specialists use modern methods for detecting neoplasms, which make it possible to identify gastrinoma of any size and location. In addition, intraoperative ultrasound techniques are used abroad, which can be used to monitor the location of the tumor during surgery.

There are cases of multiple gastrinomas, when surgical removal of tumors is almost impossible. In such cases, modern chemotherapy regimens are prescribed in accordance with international standards. After chemotherapy, the endocrinological activity of gastrinomas decreases significantly.

Simultaneously with pathogenetic treatment, symptomatic therapy is carried out. The patient is prescribed acid-reducing drugs (proton pump inhibitors, H2 receptor blockers). Moreover, standard doses of these drugs, as a rule, do not bring significant improvement to the patient. Therefore, foreign specialists select individual doses of PPIs and H2-histamine blockers for each patient. If necessary, patients take drugs that reduce acidity for life.

In cases of ineffective treatment of Zollinger-Ellison syndrome, palliative surgery is performed - gastrectomy. Removal of the stomach significantly improves the condition of patients, but gastrectomy does not cure the underlying disease.

Zollinger-Ellison syndrome is a dangerous tumor disease characterized by a triad of symptoms. The first is gastric hypersecretion. The second is peptic ulcers of the stomach, resulting from increased acidity of gastric juice, in uncharacteristic places. Healed ulcers reopen and cannot be treated with conventional medications. The third, gastrinoma, is a tumor of the islet cells of the pancreas. Gastrinoma can also be located outside the pancreas, usually in the wall of the duodenum. This tumor can be located in other organs, for example, in the bones, liver, heart, lymph nodes, ovaries.

Symptoms

  • Ulcers of the stomach, esophagus, small and duodenal intestines.
  • Sometimes diarrhea, steatorrhea (fat content in feces).
  • Pain in the upper abdominal cavity.

Causes

The cause of this disease is a tumor of the pancreas that produces gastrin, which stimulates the formation of stomach acid (hydrochloric acid). As a result of increased stomach acidity, stomach or intestinal ulcers appear.

Treatment

First of all, this syndrome is treated with medications that inhibit the intense production of stomach acid. In the absence of metastases, the tumor is removed surgically. After surgery, many patients recover completely. If there are metastases or the effect of drugs that reduce stomach acidity is ineffective, the entire stomach must be removed (gastrectomy).

The mechanism of occurrence of pancreatic tumors is not entirely clear, so nothing can be done on your own.

If you have prolonged abdominal pain in the stomach area, you should consult a doctor. First of all, patients who have previously undergone gastric surgery should consult a doctor if they develop symptoms characteristic of this disease.

Similar symptoms can be caused by other diseases. First of all, it is necessary to establish an accurate diagnosis of the disease. To do this, they take an analysis of gastric juice, perform a gastroscopy, and also determine the concentration of gastrin in the blood.

In addition, additional information is provided by angiographic images of the blood vessels supplying blood to the stomach and pancreas, as well as various tests that indicate the production of gastric juice. Today, computed tomography is widely used to detect tumors. Having established the diagnosis of the disease, the doctor will prescribe the necessary treatment or suggest surgery. Stomach infections are treated with medications that inhibit the formation of stomach acid.

Course of the disease

If pain occurs in the upper abdominal cavity (especially if it was preceded by an infectious disease), you should consult a doctor. Timely treatment reduces the likelihood of tumor development.

Zollinger-Ellison syndrome can affect people of any age, but it is more common in people between 20 and 60 years of age. With Zollinger-Ellison syndrome, ulcers of the stomach and small intestine first appear, which are not amenable to drug treatment. In addition, these ulcers appear in places that are not typical for a regular gastric ulcer. In more than 80% of patients with the above symptoms, it was possible to diagnose Zollinger-Ellison syndrome only after more than a year had passed after the onset of the disease. The pancreatic tumor that causes the disease can metastasize, so it is necessary to remove it promptly and surgically.

After gastric surgery, you must regularly visit your doctor. This must be done even if you feel well and do not have any ailments.

Early diagnosis of the disease and the presence of a single tumor increase the patient’s likelihood of recovery. With late diagnosis and delayed treatment of the syndrome, malignant pancreatic tumors are found in 60% of patients.

Zollinger-Ellison syndrome is a whole complex of symptoms that arise against the background of high levels of gastrin in the blood, which is produced by a hormonally active neoplasm. Often the tumor forms in the pancreas, but can form in the duodenum. A characteristic feature of such a tumor is that it is almost always benign, but can transform into oncology and metastasize to nearby internal organs.

At present, the mechanism of development of this disease has not yet been fully studied. However, clinicians claim that such a symptom complex is diagnosed several times more often in males than in females. The risk group consists of people from twenty to fifty years of age, but the possibility of the disease occurring in children cannot be ruled out.

There are no characteristic clinical manifestations of this disease. Often gastrinoma is expressed in intense pain, profuse diarrhea and other symptoms characteristic of other gastrointestinal ailments.

Diagnosis is based on a wide range of both instrumental and laboratory examinations. Treatment for this disorder is complex and consists of surgical intervention in combination with medication.

Etiology

Today, gastroenterologists have not fully elucidated the causes and mechanism of gastrinoma formation. However, several predisposing factors have been identified:

  • complicated heredity - clinicians have noted that such a disease can be transmitted from mother to child;
  • a genetic disease such as multiple endocrine neoplasia type 1. This disorder combines the formation of numerous small tumors without a clear location in the affected organ and peptic ulcers in the small intestine, in particular in the duodenum and small intestine;
  • hyperplasia of gastrin-producing cells of the stomach in its antrum. With this disease, gastrin secretion is not regulated in any way, which becomes the cause of uncontrolled hypergastrinemia.

Gastrinomas are single or multiple dark red nodules. They have a round or oval shape, dense consistency and small volumes - no more than two centimeters.

Classification

There is only one classification of this disorder - depending on the location of the gastrin-producing tumor. Thus, the disease can affect:

  • pancreas – in 85%;
  • antrum of the stomach – 10%;
  • duodenum – less than 5%;
  • extremely rarely such organs as the spleen and liver, gall bladder, omentum and ovaries.

Pancreatic gastrinoma, in turn, can involve in the pathological process:

  • head;
  • body;
  • the tail of this organ.

The last two localization locations are the most common.

Symptoms

During the diagnosis of Zollinger-Ellison syndrome, a peptic ulcer of the duodenum or stomach is discovered, which is resistant to antiulcer treatment. It follows from this that such a disease has practically no specific external signs. However, symptoms of Zollinger-Ellison syndrome include:

  • high intensity pain syndrome in the upper abdomen. This symptom is expressed in the vast majority of patients, namely in males. The severity of the pain increases after a meal, as when deep ulcers appear in the stomach, or immediately after sleep - on an empty stomach, which is typical for duodenal ulcer;
  • bowel dysfunction, which manifests itself in diarrhea, is a symptom of such an illness characteristic of the fairer sex. In most cases it is the only expression of the clinical picture. Fecal masses are distinguished by their abundance, watery consistency and the presence of particles of undigested food and fat;
  • heartburn and burning in the chest area - these signs are often mistaken for GERD;
  • belching with an unpleasant odor.

Doctors also identify several rarer symptoms of gastrinoma:

  • attacks of nausea and vomiting;
  • internal hemorrhages;
  • a significant decrease in body weight as the body’s response to profuse diarrhea. Often this sign indicates malignancy of a gastrin-producing tumor;
  • pallor or yellowness of the skin.

Diagnostics

To establish a final diagnosis, a wide range of laboratory and diagnostic measures will be required, which is due to the similarity of this disorder with other diseases of the digestive system.

Primary diagnosis is aimed at performing:

  • detailed patient interview;
  • familiarizing the doctor with the patient’s medical history and life history;
  • a thorough physical examination, which must include palpation of the abdomen.

This is what will enable the gastroenterologist to learn more about the factors in the formation, presence and intensity of the symptoms of such a disease.

Laboratory diagnostic techniques include:

  • general and biochemical blood test;
  • clinical urine analysis;
  • microscopic examination of stool - paying attention to the consistency and amount of fat in the stool;
  • determination of gastrin concentration in the blood;
  • performing secretin and calcium tests;
  • breath test to detect the bacteria Helicobacter pylori.

However, the most valuable methods for instrumental diagnosis of Zollinger-Ellison syndrome are:

  • FEGDS - for examining and assessing the condition of the inner surface of the mucous layer of the esophagus, stomach and the initial part of the duodenum;
  • A biopsy is the removal of a small piece of the affected organ, which is carried out during a previous procedure. The need for a biopsy is to determine the malignant or benign course of the disease;
  • Ultrasound of the abdominal organs - to confirm the location of the gastrin-producing tumor;
  • CT and MRI.

To establish the correct diagnosis using the diagnostic measures described above, the gastroenterologist must differentiate gastrinoma from the following ailments:

  • ulcers of the upper gastrointestinal tract, which scar poorly and often recur;
  • celiac disease;
  • malignant or benign tumors of the small intestine;
  • gastritis.

Treatment

Drug treatment for Zollinger-Ellison syndrome is aimed at reducing the production of acidic gastric contents, which can be achieved by taking:

  • histamine H2 receptor blockers, PPIs;
  • selective M-anticholinergics.

If conservative therapy is ineffective, they resort to surgical treatment, which is performed in several ways:

  • complete removal of the tumor. However, due to the fact that metastases are detected during surgery, complete cure using such operable tactics is achieved only in every third patient with a similar diagnosis;
  • excision of the stomach using selective vagotomy and pyloroplasty - has low effectiveness, because ulcers may be prone to relapse;
  • total gastrectomy – indicated only if complications develop.

In cases where gastrinoma has become malignant, as well as in those patient conditions where surgery is impossible, chemotherapy is used.

Complications

Since ulcers in Zollinger-Ellison syndrome are resistant to standard antiulcer therapy, they are very often prone to developing complications that can threaten the patient's life. These include:

  • ulcer perforation;
  • diffuse peritonitis;
  • formation of strictures;
  • hemorrhages;
  • loss of body weight to the point of extreme exhaustion;
  • dysfunction of the heart;
  • spread of gastrinoma metastases to regional internal organs;
  • compression of the bile ducts.

Prevention

There are no specific preventive measures against the formation of Zollinger-Ellison syndrome. However, people need to adhere to the following rules:

  • proper and rational nutrition - this means minimizing the consumption of fatty and spicy foods, smoked and fast food, carbonated drinks and coffee;
  • completely give up bad habits;
  • If possible, avoid stressful situations and nervous tension;
  • undergo regular examinations with a gastroenterologist.

The prognosis for this disease is only slightly better than for other malignant neoplasms. Five-year survival rate in the presence of metastases reaches 50–80%, after surgical treatment – ​​70–80%.

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Zollinger-Ellison syndrome is a condition that occurs as a result of an increased concentration of the hormone gastrin produced by a tumor (gastrinoma), located in most cases in the pancreas or duodenum. An increased content of gastrin leads to gastric hypersecretion, which initiates the formation of multiple peptic and duodenal ulcers of the gastrointestinal tract, which are difficult to treat. Gastrinomas are often malignant and prone to metastasis.

Causes of Zollinger-Ellison syndrome

The main cause of the syndrome is uncontrollable, persistent hypergastrinemia (increased gastrin content), which appears as a result of excessive secretion of the hormone by a gastrin-producing tumor (gastrinoma). This provokes an increase in the production of hydrochloric acid, enzymes and gastric juice, leading to the occurrence of ulcerative defects with atypical localization.

In Zollinger-Ellison syndrome, gastrinomas are located in 90% of the pancreas and the walls of the duodenum; they can also be found in the stomach, spleen, and liver. The reasons that cause the formation of gastrinoma are not precisely known - a hereditary predisposition, expressed by endocrine neoplasia, of a multiple nature is assumed. The syndrome is a rare pathology (3-4 cases per year per 1 million people), more often affecting men aged 25-50 years. Gastrinomas are small-sized formations, most often less than 1 cm; half of the patients have multiple tumors, more than 60-80% of them become malignant and very slow growth is noted.

Symptoms of Zollinger-Ellison syndrome

The disease in the early stages of development manifests itself with signs inherent in ulcerative lesions of the stomach or duodenum. The difference from peptic ulcer disease is severe pain in the upper abdomen, characterized by resistance and tolerance to antiulcer drugs. The most characteristic, and sometimes the only symptom of Zollinger-Ellison syndrome is diarrhea, which occurs due to increased peristalsis, reflux of acidic contents into the small intestine, the formation of inflammatory processes and impaired absorption. In this case, the presence of copious, semi-formed, watery stools containing undigested food and fat is noted. More rare signs of the disease include:

  • Intense heartburn;
  • Belching;
  • Manifestations of esophagitis;
  • Vomiting;
  • Nausea;
  • Gastrointestinal bleeding;
  • Perforation of ulcers.

Also a symptom of the pathology is significant weight loss by the patient, which may also be a sign of a malignant form of gastrinoma in Zollinger-Ellison syndrome.

Diagnosis of the disease

For successful treatment of Zollinger-Ellison syndrome, it is extremely important to diagnose it promptly and correctly. Early detection of the pathology is complicated by the similarity of its symptoms to peptic ulcer disease; it is also difficult to detect the localization of tumors due to their often large number and small size. Suspicions of the presence of gastrinoma should arise when traditional treatment of ulcerative defects is ineffective, their atypical location and tendency to relapse.

To diagnose the disease, it is important to study the fasting level of gastrin in the blood serum and in gastric secretion, which is possible when conducting tests with a standardized volume of food or intravenous administration of calcium salts, secretin or glucagon. When using calcium gluconate in patients suffering from Zollinger-Ellison syndrome, the concentration of gastrin increases by more than one and a half times. With intravenous injections of glucagon and secretin, the initial level of the test hormone increases by an average of 70%, and when tested with standardized food it remains unchanged.

Also, when diagnosing pathology, the following is carried out:

  • X-ray of the stomach;
  • Ultrasonography;
  • Ultrasound of the abdominal organs;
  • Computed tomography.

The most accurate and at the same time technically complex research methods include selective abdominal angiography, which allows one to determine the level of gastrin in blood taken from the pancreatic veins.

Treatment of Zollinger-Ellison syndrome

When treating the syndrome, they resort to both conservative and surgical methods. Conservative therapy includes the use of histamine H2 receptor blockers (famotidine, ranitidine), proton pump inhibitors (omeprazole, lansoprazole, etc.). The drugs are prescribed in high doses necessary for the fastest healing of ulcerative defects. In some cases, combinations of H2 receptors with selective m-anticholinergics (platiphylline, pirenzepine) are used. Therapy is long-term, sometimes the use of medications is indicated for life due to the threat of relapse of ulcerations.

Surgery is resorted to if drug therapy is ineffective. Surgical treatment of Zollinger-Ellison syndrome involves complete removal of the gastrinoma, which is possible only in 20% of patients due to the discovery of metastases at the time of surgery. Total gastrectomy, which was most often used in the past, is currently performed only for complications of the ulcerative process. If the tumor is inoperable and malignant, chemotherapy is prescribed.

Prognosis for Zollinger-Ellison syndrome is more optimistic than for other malignancies and is based on the rather slow growth of gastrinoma. The lethal outcome is often stated not due to the tumor itself, but due to the development of complications of ulcerative lesions.