Insulinoma

Description:

Insulinoma is the most widespread endocrine tumor of a pancreas. 70-75% of hormonal and active tumors of this body fall to its share. Insulinoma is solitary and multiple, in 1-5% of cases the tumor is a component of multiple endocrine adenomatosis. It can arise at any age, but a thicket - persons have 40-60 years, and with an identical frequency at men and women. Benign tumors prevail (approximately in 90% of cases). Insulinoma can be localized in any part of a pancreas. Approximately at 1% of patients it is located ekstrapankreatichesk - in an epiploon, a wall of a stomach, duodenum, a hilus lienis and other areas. The sizes of a tumor vary from several millimeters to 15 cm in the diameter, making 1-2 cm are more often.
The bulk of cells in a tumor is made by V-cells, but also A-cells, cells without secretory granules, similar to cells of output channels meet. The malignant insulinoma can give metastasises in various bodies, but most often in a liver.

The major pathogenetic factors at an insulinoma are uncontrollable production and secretion of insulin, irrespective of the content of glucose of blood (at the raised products of insulin ability to deposit their pro-peptide and peptide is reduced by tumor cells). The hypoglycemia arising owing to a hyper dysinsulinism causes the majority of clinical symptoms.

Along with insulin cells of an insulinoma also other peptides - a glucagon, software can be produced in the increased quantities.

Insulinoma reasons:

Soon after opening by Banting and Vest of insulin in 1921 symptoms of its overdose at a clinical use of commercial drugs at patients with a diabetes mellitus became known. It allowed Harris to formulate a concept about the spontaneous hypoglycemia caused by hypersecretion of this hormone. Numerous attempts of identification and treatment by insulin were made in 1929 when Graham for the first time was succeeded to remove an insulinsekretiruyushchy tumor successfully. Since then in the world literature there are messages approximately on 2000 patients with the functioning beta and cellular new growths.

Does not raise doubts that symptoms of an insulinoma are connected with its hormonal activity. The hyper dysinsulinism is the main pathogenetic mechanism on which all symptom complex of a disease depends. Continuous secretion of insulin, without submitting to the physiological mechanisms regulating a homeostasis concerning glucose leads to development of a hypoglycemia, glucose of blood is necessary for normal life activity of all bodies and fabrics, especially a brain which bark uses it more intensively, than all other bodies. About 20% of all glucose coming to an organism are spent for function of a brain. Special sensitivity of a brain to a hypoglycemia is explained by the fact that contrary to almost all body tissues the brain has no reserves of carbohydrates and is not capable to use as a power source the circulating free fatty acids. At the termination of receipt in bark of big cerebral hemispheres of glucose for 5-7 min. in its cells there are irreversible changes, at the same time the most differentiated bark elements perish.

At decrease in level of glucose to a hypoglycemia the mechanisms directed to a glycogenolysis, a gluconeogenesis, mobilization of free fatty acids, a ketogenesis turn on. In these mechanisms 4 hormones - noradrenaline, a glucagon, cortisol and a growth hormone participate in the basic. Apparently, only the first of them causes clinical manifestations. If reaction to a hypoglycemia emission of noradrenaline comes quickly, then the patient has a weakness, a tremor, tachycardia, perspiration, concern and feeling of hunger; symptoms from the central nervous system include dizziness, a headache, doubling in eyes, a behavior disorder, a loss of consciousness. When the hypoglycemia develops gradually, the changes connected with TsNS, and reactive prevail (on noradrenaline) the phase can be absent.

Insulinoma symptoms:

Insulinoma symptoms are included, as a rule, in a varying degree by both groups of symptoms, however existence of psychological disturbances and small awareness of doctors on this disease often lead to what owing to diagnostic mistakes patients from insulinomy is long and are unsuccessfully treated under the most various diagnoses. Wrong diagnoses put at % of patients from insulinomy.

Insulinoma symptoms, as a rule, are considered with emphasis on manifestations of hypoglycemic attacks though in the mezhpristupny period there are symptoms reflecting the damaging influence of a chronic hypoglycemia on the central nervous system. These defeats consist in insufficiency VII and XII couples of cranial nerves on the central type"; asymmetries of tendon and periosteal jerks. Sometimes it is possible to reveal pathological Babinski's reflexes, Rossolimo, Marinesku-Radovich. At a part of patients symptoms of pyramidal insufficiency without pathological reflexes are noted. Disturbance of higher nervous activity in the mezhpristupny period is expressed in decrease in memory and intellectual working capacity, loss of professional skills that quite often forces patients to be engaged in less skilled work.

The period of an acute hypoglycemia is a result of failure of kontrinsulyarny factors and the TsNS adaptation properties. Most often the attack develops early morning hours that is connected with a long (night) break in meal. Usually patients cannot "wake up". It is not a dream, and the disorder of consciousness of various depth replacing it any more. A long time they remain disoriented, make the unnecessary repeating movements, in monosyllables answer the elementary questions. The epileptiform attacks observed at these patients differ from true in the bigger duration, horeoformny convulsive twitchings, hyperkinesias, plentiful neurovegetative symptomatology. Despite the long course of a disease, at patients there do not occur the harakteriologichesky changes of the personality described at epileptics.

Quite often hypoglycemic states at patients from insulinomy are shown by attacks of psychomotor excitement: one rush about, cry out something, threaten someone; others - sing, dance, beside the point answer questions, make an impression of got drunk. The hypoglycemia at an insulinoma can sometimes be shown by a snopodobny state: patients leave or leave in the uncertain direction and then cannot explain how they appeared there. Some make antisocial conducts - recover at the first need, enter various unmotivated conflicts, can pay off instead of money with any objects. Progressing of an attack most often comes to an end with deep disorder of consciousness out of which patients are brought intravenous injection of solution of glucose. If help is not given, then the hypoglycemic attack can last from several hours to several days. Patients cannot tell about character of an attack as they do not remember the incident - retrograde amnesia.

The hypoglycemia caused by insulinomy develops on an empty stomach. Symptoms are artful and can remind various psychiatric and neurologic disturbances. Disturbances from TsNS include a headache, confusion of consciousness, a hallucination, muscular weakness, paralysis, an ataxy, changes of the personality and, perhaps, when progressing a loss of consciousness, an epileptic seizure and a coma. Symptoms from a vegetative part of the nervous system (dizziness, weakness, a tremor, heartbeat, perspiration, feeling of hunger, the increased appetite, nervousness) often are absent.

Diagnosis of an insulinoma:

In diagnosis of an insulinoma use functional trials. Distribution was gained by the test with starvation within a day and with purpose of a low-calorie diet (with restriction of carbohydrates and fats) for 72 h. At patients from insulinomy hypoglycemia symptoms develop, but even at their absence concentration of glucose in blood lower than 2,77 mmol/l during the day is registered. Insulinoma cells independently produce insulin irrespective of the content of glucose in blood, and coefficient insulin/glucose is high (due to decrease in content of glucose and increase in level of insulin) that is pathognomonic. Diagnostic accuracy of the test with starvation of nearly 100%.

Use also insulinosupressivny test. Administration of exogenous insulin induces a hypoglycemic state. The decrease in concentration of glucose of blood caused by exogenous insulin is normal, leads to suppression of release of endogenous insulin and S-peptide. Cells of an insulinoma continue to produce hormone. The high levels of S-peptide disproportionate to low concentration of glucose demonstrate existence of an insulinoma. The diagnostic value of the test is so high, as well as tests with starvation. The lack of these tests - at patients with insulinomy is not possible to avoid development of a hypoglycemia and neuroglucosinging that demands stationary conditions for their carrying out.

The Insulinprovokatsionny test is directed to release of endogenous insulin by intravenous administration of glucose (0,5 g/kg) or a glucagon (1 mg) or sugar-lowering derivatives of sulphonylurea (for example, Tolbutamidum in a dose of 1 g). But increase in serumal insulin at patients from insulinomy is significantly higher, than at healthy faces, only in 60-80% of cases. Frequency of positive test of stimulation of release of insulin considerably increases at simultaneous administration of glucose and calcium (5 mg/kg). Cells of an insulinoma are more sensitive to irritation calcium, than normal V-cells. Besides, at this test development of a hypoglycemia by infusion of glucose is compensated.

Along with definition  the radio immune research of pro-insulin can help with natoshchakovy serum of glucose, insulin and S-peptide in diagnosis of an insulinoma. However the giperproinsulinemiya is possible not only at patients with an organic hyper dysinsulinism, but also at patients with uraemia, cirrhosis, a thyrotoxicosis, at the persons which accepted insulin or sugar-lowering drugs, for example, with the suicide purpose.

Differentiate conditions of a spontaneous hypoglycemia from extra pancreatic diseases without existence of a hyper dysinsulinism: from pituitary and/or adrenal insufficiency, severe damages of a liver (insufficient products of glucose), ekstrapankreatichesky malignant tumors, for example from a big fibrosarcoma (the increased glucose consumption), a galactosemia and diseases of accumulation of a glycogen (enzymatic insufficiency), from TsNS diseases (insufficient consumption of carbohydrates). Diagnosis is helped clinical also by the datas of laboratory caused by each of above-mentioned groups of diseases. In their differentiation from insulinomy apply definition of immunoreactive insulin and S-peptide in blood on an empty stomach along with determination of content of glucose and conducting test with intravenous administration of glucose and calcium. Giperinsulinemiya and positive character of the insulinoprovokatsionny test will testify in favor of an insulinoma. Tests with starvation and a hypocaloric diet in some cases are contraindicated (for example, at primary or secondary hypocorticoidism).

It is necessary to carry out differential diagnosis between an organic hypoglycemia and toxic (the alcoholic, and also medicamentous, caused by administration of insulin or sugar-lowering derivatives of sulphonylurea). The alcoholic hypoglycemia proceeds without giperinsulinemiya. Administration of exogenous insulin or sugar-lowering drugs leads to the increased content of immunoreactive insulin in blood at the normal or lowered S-peptide level as both peptides are formed in equimolar quantities of pro-insulin and come to a blood stream.

At reactive (postprandialny) forms of a hyper dysinsulinism - the raised tone of a vagus nerve, diabetes mellitus prestages, a late dumping syndrome - on an empty stomach the size of glucose of blood is normal.

The hyperplasia of insulotsit - незидиобластоз which can be the cause of an organic hypoglycemia (nesidioblasts - epithelial cells of the small pancreatic courses which are differentiated in insulinkompetentny cells occasionally occurs at newborns and small children). At small children незидиобластоз on the basis of clinical and datas of laboratory it is indistinguishable from an insulinoma.

Treatment of an insulinoma:

In general efficiency of surgical treatment of an insulinoma reaches 90%. Operational mortality makes 5-10%.  Small single superficial insulinoma of a pancreas enukliirutsya usually in the surgical way. If adenoma single, but the big sizes is also localized deeply in tissue of a body or tail of gland if multiple formations of a body or tail are revealed (or both) if the insulinoma is not found (an uncharacteristic circumstance), the distapny, subtotal pancreatectomy is carried out. Less than in 1% of cases the ectopic localization of an insulinoma located in a peripancreatic zone of a wall of a duodenum or in periduodenalny area is observed; in this case detection of a tumor is possible only by careful search during surgery. At proximal localization malignizirovanny resectable insulin showed a pankreatoduodenalny resection (Whipple's operation). The total pancreatectomy is carried out in case of inefficiency of a subtotal pankreatektmoiya.

If the hypoglycemia remains, it is possible to use diazoxide from an initial dose of 1,5 mg/kg orally 2 times a day together with natriuretika. The dose can be increased to 4 mg/kg. The somatostatin analog октреотид (100-500 mkg subcutaneously 2-3 times a day) not always is effective and its use should be considered at patients with the proceeding hypoglycemia, unreceptive to diazoxide. It was to patients who have a treatment oktreotidy effective, it is possible to appoint drug intramusculary of 20-30 mg once a day. At use of an oktreotid patients need to appoint in addition pancreatic enzymes as it suppresses secretion of pancreatic enzymes. Verapamil, diltiazem and Phenytoinum belong to other drugs rendering small and variable effect on insulin secretion.

If symptoms of an insulinoma remain, it is possible to use chemotherapy, but its efficiency is limited. Streptozototsin is effective in 30% of cases, and in a combination with 5-ftoruratsily efficiency reaches 60% with a duration to 2 years. Treat other drugs doxorubicine, хлорозотоцин and interferon.