Insulinoma

Insulinoma is the most common endocrine tumor of the pancreas. It accounts for 70-75% of hormone-active tumors of this organ. Insulinoma is solitary and multiple, in 1-5% of cases, the tumor is a component of multiple endocrine adenomatosis. It can occur at any age, but more often - in individuals 40-60 years old, with the same frequency in men and women. Prevalent benign tumors (approximately 90% of cases). Insulinoma can be localized in any part of the pancreas. Approximately in 1% of patients it is located extrapancreatic - in the epiploon, the wall of the stomach, duodenum, gates of the spleen and other areas. The size of the tumor varies from a few millimeters to 15 cm in diameter, making up more often 1-2 cm.

The majority of cells in the tumor are B cells, but there are also A-cells, cells without secretory granules, similar to the cells of the excretory ducts. Malignant insulinoma can give metastases to various organs, but more often to the liver.

The main pathogenetic factors in insulin are uncontrolled production and secretion of insulin, regardless of the blood glucose content (with increased production of insulin by tumor cells, their ability to deposit the propeptide and the peptide is reduced). The resultant hyperinsulinism hypoglycemia accounts for the majority of clinical symptoms.

Along with insulin, insulinoma cells can be produced in high amounts and other peptides - glucagon, PP.

Insulinoma - a tumor of the beta cells of the islets of Langerhans, secreting an excessive amount of insulin, which manifests itself as a hypoglycemic symptom complex. In the literature, you can find the following names of the disease: insuloma, hypoglycemic disease, organic hypoglycemia, Harris syndrome, organic hyperinsulinism, insulin secretion aphom. The current term is the term insulinoma. Insulin secretion is described in all age groups - from newborns to the elderly, but more often it affects the most able-bodied - from 30 to 55 years. Among the total number of sick children account for about 5%.

[1], [2], [3], [4], [5], [6], [7], [8]

Causes of the insulinoma

What causes insulinoma?

Soon after the discovery of insulin by Bunting and Westing in 1921, the symptoms of his overdose became known with the clinical use of commercial drugs in diabetic patients. This allowed Harris to formulate the concept of spontaneous hypoglycemia, caused by increased secretion of this hormone. Numerous attempts to detect and treat insulin were carried out in 1929, when Graham was the first to successfully remove the insulin secretory tumor .. Since then, about 2000 patients with functioning beta-cell tumors have been reported in the world literature.

There is no doubt that insulinoma symptoms are associated with its hormonal activity. Hyperinsulinism is the main pathogenetic mechanism on which the whole symptom complex of the disease depends. The constant secretion of insulin, not submitting to the physiological mechanisms regulating homeostasis against glucose, leads to the development of hypoglycemia, blood glucose is necessary for normal vital activity of all organs and tissues, especially the brain whose bark uses it more intensively than all other organs. The function of the brain consumes about 20% of all glucose entering the body. The special sensitivity of the brain to hypoglycemia is explained by the fact that, in contrast to almost all tissues of the body, the brain does not have carbohydrate stores and is unable to use circulating free fatty acids as an energy source. With the cessation of the admission of glucose to the cortex of the cerebral hemispheres for 5-7 minutes, irreversible changes occur in its cells, with the most differentiated elements of the cortex being killed.

With a decrease in glucose levels before hypoglycemia, mechanisms aimed at glycogenolysis, gluconeogenesis, mobilization of free fatty acids, ketogenesis are included. In these mechanisms, mainly 4 hormones participate - norepinephrine, glucagon, cortisol and growth hormone. Apparently, only the first of them causes clinical manifestations. If the reaction to hypoglycemia with norepinephrine release occurs quickly, the patient develops weakness, tremor, tachycardia, sweating, anxiety and hunger; symptoms from the central nervous system include dizziness, headache, double vision, impaired behavior, loss of consciousness. When hypoglycemia develops gradually, then the changes associated with the central nervous system prevail, and the reactive (for norepinephrine) phase may be absent.

Symptoms of the insulinoma

Symptoms of insulinoma

Symptoms of insulin usually include to some extent both groups of symptoms, but the presence of neuropsychiatric disorders and low awareness of the doctors about this disease often lead to the fact that due to diagnostic errors, patients with insulinoma are treated for a long time and unsuccessfully under a variety of diagnoses. Erroneous diagnoses are given in% of patients with insulinoma.

Symptoms of insulinoma, as a rule, are considered with an emphasis on the manifestations of hypoglycemic attacks, although in the interictal period there are symptoms reflecting the damaging effect of chronic hypoglycemia on the central nervous system. These lesions consist in the deficiency of VII and XII pairs of cranial nerves according to the central type "; asymmetry of tendon and periosteal reflexes. Sometimes it is possible to reveal pathological reflexes of Babinsky, Rossolimo, Marinescu-Radovic. Part of the patients have symptoms of pyramidal insufficiency without pathological reflexes. Violation of higher nervous activity in the interictal period is expressed in a decrease in memory and mental capacity for work, loss of professional skills, which often forces patients to engage in less skilled work.

Erroneous diagnoses in patients with insulinoma

Diagnosis	%
Epilepsy	34
A brain tumor	15
Violation of cerebral circulation	15
Vegetosovascular dystonia	Eleven
Diencephalic syndrome	9
Psychosis	5
Residual phenomena of neuroinfections	3
Neurasthenia	3
Intoxication	2
Poisoning and others	3

The period of acute hypoglycemia is the result of disruption of the contrinular factors and the adaptive properties of the central nervous system. Most often, the attack develops in the early morning hours, which is associated with a long (night) break in eating. Usually patients can not "wake up". This is no longer a dream, but a disorder of consciousness of different depths, replacing it. For a long time they remain disoriented, produce unnecessary repetitive movements, monosyllables answer the simplest questions. Observed in these patients epileptiform seizures differ from the true longer duration, choreoform convulsive twitching, hyperkinesis, abundant neurovegetative symptoms. Despite the long course of the disease, patients do not experience any characterological changes in the personality described in epileptics.

Often, hypoglycemic conditions in patients with insulinoma are manifested by attacks of psychomotor agitation: some rush, shout something, threaten someone; others - sing, dance, do not essentially answer questions, give the impression of intoxicated. Sometimes hypoglycemia with insulinoma can manifest a dreamlike state: the patients leave or go in an indefinite direction and then can not explain how they ended up there. Some commit antisocial actions - recover at the first necessity, enter into various unmotivated conflicts, can pay for money instead of money with any objects. Progression of an attack often results in a deep consciousness disorder, from which patients are withdrawn by intravenous infusion of a glucose solution. If no help is provided, the hypoglycemic attack can last from a few hours to several days. About the nature of the attack, patients can not tell, because they do not remember what happened - retrograde amnesia.

Hypoglycemia caused by insulinoma develops on an empty stomach. Symptoms are insidious and can resemble various psychiatric and neurological disorders. CNS disorders include headache, confusion, hallucinations, muscle weakness, paralysis, ataxia, personality changes and, possibly, progression, loss of consciousness, epileptic fit and to whom. Symptoms from the vegetative part of the nervous system (dizziness, weakness, tremor, palpitation, sweating, hunger, increased appetite, nervousness) are often absent.

Symptoms of insulinoma

Diagnostics of the insulinoma

Diagnosis of insulinoma

Functional tests are used to diagnose insulinoma. The spread was tested with fasting during the day and with the appointment of a low-calorie diet (with restriction of carbohydrates and fats) for 72 hours. Patients with insulinoma develop symptoms of hypoglycemia, but even in their absence during the day, the blood glucose concentration is recorded below 2.77 mmol / l. Insulinoma cells autonomously produce insulin regardless of the glucose content in the blood, and the insulin / glucose ratio is high (by lowering glucose and increasing insulin levels), which is pathognomonic. Diagnostic accuracy of the test with starvation is almost 100%.

An insulin suppressive test is also used. The introduction of exogenous insulin induces a hypoglycemic state. Normally, a decrease in the blood glucose concentration caused by exogenous insulin results in a suppression of the release of endogenous insulin and the C-peptide. Insulinoma cells continue to produce a hormone. High levels of C-peptide, disproportionate to low glucose concentration, indicate the presence of insulinoma. The diagnostic value of the test is as high as that of a fasting test. The lack of these samples - in patients with insulinoma it is impossible to avoid the development of hypoglycemia and neuroglucopenia, which requires stationary conditions for their conduct.

The insulin provocation test aims to release endogenous insulin by intravenous glucose (0.5 g / kg) or glucagon (1 mg) or sugar-reducing sulfonylureas (eg tolbutamide, 1 g). But the increase in serum insulin in patients with insulinoma is significantly higher than in healthy individuals, only in 60-80% of cases. The frequency of a positive insulin release stimulation test is significantly increased with simultaneous administration of glucose and calcium (5 mg / kg). Insulinoma cells are more sensitive to calcium irritation than normal B cells. In addition, this test compensates for the development of hypoglycemia by glucose infusion.

Along with the determination of glucose, insulin and C-peptide in the fasting serum in the diagnosis of insulinoma, a radioimmune study of proinsulin can help. However, hyperproinsulinemia is possible not only in patients with organic hyperinsulinism, but also in patients with uremia, cirrhosis, thyrotoxicosis, in people who have taken insulin or sugar-reducing drugs, for example, with a suicidal goal.

Differentiate the states of spontaneous hypoglycemia from extra-pancreatic diseases without the presence of hyperinsulinism: from pituitary and / or adrenal insufficiency, severe liver damage (insufficient production of glucose), extrapancreatic malignant tumors, for example from large fibrosarcoma (increased glucose intake), galactosemia and glycogen storage diseases (enzyme deficiency ), from diseases of the central nervous system (insufficient intake of carbohydrates). Clinical and laboratory data, due to each of the above-mentioned disease groups, help diagnosis. In distinguishing them from insulinoma, the definition of immunoreactive insulin and C-peptide in fasting blood is used along with the determination of the glucose content and the conduct of a sample with intravenous administration of glucose and calcium. Hyperinsulinemia and the positive nature of the insulin-provoking test will testify in favor of insulinoma. Tests with starvation and hypocaloric diet in some cases are contraindicated (for example, with primary or secondary hypocorticism).

A differential diagnosis should be made between organic hypoglycemia and toxic (alcoholic, as well as medicinal, induced by the introduction of insulin or sugar-reducing derivatives of sulfonylureas). Alcoholic hypoglycemia occurs without hyperinsulinemia. The introduction of exogenous insulin or sugar reducing drugs leads to an increased content of immunoreactive insulin in the blood at normal or decreased levels of C-peptide, since both peptides are formed in equimolar amounts from proinsulin and enter the bloodstream.

With reactive (postprandial) forms of hyperinsulinism - increased vagal tone, diabetes mellitus, late dumping syndrome - fasting blood glucose is normal.

In infants and small children, insulocyte hyperplasia is occasionally found - nezidioblastosis, which can cause organic hypoglycemia (nezidioblasti - epithelial cells of small pancreatic passages that differentiate into insulin-competent cells). In young children, nezidioblastosis, on the basis of clinical and laboratory data, is indistinguishable from insulinoma.

Diagnosis of insulinoma

[9], [10], [11]

Treatment of the insulinoma

Treatment of insulinoma

In general, the effectiveness of surgical treatment of insulinoma reaches 90%. The operational mortality rate is 5-10%. Small single surface insulinoma of the pancreas is usually enucleated surgically. If the adenoma is single, but large, and is located deep in the tissue of the body or tail of the gland, if multiple body or tail formations (or both) are detected, if an insulinoma is not detected (uncharacteristic circumstance), a dystopic, subtotal pancreatectomy is performed. In less than 1% of cases, ectopic localization of insulinoma occurs in the peripancreatic zone of the duodenal wall or in the periduodenal region; in this case, detection of the tumor is possible only with a careful search during a surgical operation. With proximal localization of malignant operable insulin, pancreatoduodenal resection (Whipple's operation) is indicated. Total pancreatectomy is performed in the case of ineffectiveness of subtotal pancreatectomy.

If hypoglycemia persists, diazoxide can be used from the initial dose of 1.5 mg / kg orally 2 times daily with sodium nares. The dose may be increased to 4 mg / kg. The somatostatin analogue octreotide (100-500 μg subcutaneously 2-3 times a day) is not always effective and its use should be considered in patients with ongoing hypoglycemia, resistant to diazoxide. Patients in whom treatment with octreotide proved effective, you can prescribe the drug intramuscularly 20-30 mg once a day. When octreotide is used, patients should additionally be assigned pancreatic enzymes, as it inhibits the secretion of pancreatic enzymes. Other drugs that have a small and variable effect on insulin secretion include verapamil, diltiazem and phenytoin.

If the symptoms of insulinoma persist, you can use chemotherapy, but its effectiveness is limited. Streptozotocin is effective in 30% of cases, and in combination with 5-fluorouracil, the efficacy reaches 60% with a duration of up to 2 years. Other drugs include doxorubicin, chlorozotocin, and interferon.

Treatment of insulinoma