Insulinoma of the pancreas is a disease that requires timely treatment. Hormonally active formation or insulinoma of the pancreas: symptoms, methods of treatment and removal of the tumor

- a hormonally active tumor of β-cells of the pancreatic islets, secreting insulin in excess and leading to the development of hypoglycemia. Hypoglycemic attacks with insulinoma are accompanied by trembling, cold sweat, hunger and fear, tachycardia, paresthesia, speech, visual and behavioral disorders; in severe cases, convulsions and coma. Diagnosis of insulinoma is carried out using functional tests, determining the level of insulin, C-peptide, proinsulin and blood glucose, ultrasound of the pancreas, selective angiography. With insulinoma, surgical treatment is indicated - tumor enucleation, pancreatic resection, pancreatoduodenal resection or total pancreatectomy.

Neurological examination in patients with insulinoma reveals asymmetry of periosteal and tendon reflexes, irregularity or decrease in abdominal reflexes, pathological reflexes of Rossolimo, Babinsky, Marinescu-Radovich, nystagmus, paresis of upward gaze, etc. Due to the polymorphism and nonspecificity of clinical manifestations, patients with insulinoma may be given erroneous diagnoses of epilepsy, brain tumor, vegetovascular dystonia, stroke, diencephalic syndrome, acute psychosis, neurasthenia, residual effects of neuroinfection, etc.

Diagnosis of insulinoma

To establish the causes of hypoglycemia and differentiate insulinoma from other clinical syndromes allows a set of laboratory tests, functional tests, imaging instrumental studies. The fasting test is aimed at provoking hypoglycemia and causes the Whipple triad pathognomonic for insulinoma: a decrease in blood glucose to 2.78 mmol / l or lower, the development of neuropsychic manifestations against the background of starvation, the possibility of arresting an attack by oral administration or intravenous infusion of glucose.

In order to induce a hypoglycemic state, an insulin suppressive test with the introduction of exogenous insulin can be used. At the same time, inadequately high concentrations of C-peptide in the blood are noted against the background of extremely low glucose levels. Conducting an insulin provocation test (intravenous administration of glucose or glucagon) promotes the release of endogenous insulin, the level of which in patients with insulinoma becomes significantly higher than in healthy individuals; while the ratio of insulin and glucose exceeds 0.4 (normally less than 0.4).

With positive results of provocative tests, topical diagnosis of insulinoma is performed: ultrasound of the pancreas and abdominal cavity, scintigraphy, MRI of the pancreas, selective angiography with blood sampling from the portal veins, diagnostic laparoscopy, intraoperative ultrasonography of the pancreas. Insulin has to be differentiated from drug and alcohol hypoglycemia, pituitary and

Most pancreatic diseases directly affect carbohydrate metabolism. Insulinoma increases the production of insulin in the body. When carbohydrates in habitual food are not enough to cover this excessive secretion, a person develops. It develops very slowly, often unnoticed by the patient, gradually damaging the nervous system. Due to the complexity of diagnosis and the rarity of insulinoma, a patient may be treated by a neurologist or psychiatrist for several years without results until the symptoms of hypoglycemia become apparent.

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What is insulinoma

Among other important functions, the pancreas provides our body with hormones that regulate carbohydrate metabolism - insulin and glucagon. Insulin is responsible for removing sugar from the blood to the tissues. It is produced by a special kind of cells that are located in the tail of the pancreas, called beta cells.

Insulinoma is a neoplasm consisting of these cells. It belongs to hormone-secreting tumors and is able to independently synthesize insulin. The pancreas releases this hormone when the concentration of glucose in the blood increases. The tumor produces it always, without regard to physiological needs. The larger and more active the insulinoma, the more insulin it produces, which means that blood sugar decreases more.

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This tumor is rare, affecting one in 1.25 million people. Most often it is small, up to 2 cm, located in the pancreas. In 1% of cases, insulinoma can be located on the wall of the stomach, duodenum, spleen, liver.

A tumor only half a centimeter in diameter is capable of producing an amount of insulin that will cause glucose to drop below normal. At the same time, it is quite difficult to detect it, especially with atypical localization.

Insulinoma most often affects adults of working age, women 1.5 times more often.

Most often, insulinomas are benign (ICD-10 code: D13.7), after exceeding the size of 2.5 cm, signs of a malignant process begin in only 15 percent of neoplasms (code C25.4).

Why develop and how

The exact cause of insulinoma development is unknown. There are suggestions about the presence of a hereditary predisposition to pathological cell growth, about single failures in the adaptive mechanisms of the body, but these hypotheses have not yet been scientifically confirmed. Only the connection of insulinoma with multiple endocrine adenomatosis, a rare genetic disease in which hormone-secreting tumors develop, has been precisely established. In 80% of patients, formations are observed in the pancreas.

Insulinomas can have any structure, and areas within the same tumor often differ. This is due to the different ability of insulin to produce, store and secrete insulin. In addition to beta cells, the tumor may contain other pancreatic cells that are atypical and functionally inactive. Half of the neoplasms, in addition to insulin, are also capable of producing other hormones - pancreatic polypeptide, glucagon, gastrin.

Less active insulinomas are thought to be larger and more likely to become malignant. Perhaps this is due to less severe symptoms and late detection of the disease. The frequency of hypoglycemia and the rate of increase in symptoms are directly related to tumor activity.

The autonomic nervous system suffers from a lack of glucose in the blood, the functioning of the central nervous system is disrupted. Periodically, low blood sugar affects higher nervous activity, including thinking and consciousness. It is with damage to the cerebral cortex that the often inadequate behavior of patients with insulinoma is associated. Metabolic disorders lead to damage to the walls of blood vessels, due to which cerebral edema develops and blood clots form.

Signs and symptoms of insulinoma

Insulinoma produces insulin constantly, and pushes it out of itself with a certain frequency, so episodic attacks of acute hypoglycemia are replaced by relative calm.

Also, the severity of the symptoms of insulinoma is affected by:

Features of nutrition. Sweet lovers will feel problems in the body later than adherents of protein foods.
Individual sensitivity to insulin: some people pass out when blood sugar is less than 2.5 mmol / l, others can withstand such a decrease normally.
The composition of the hormones that the tumor produces. With a large amount of glucagon, symptoms will appear later.
tumor activity. The more hormone is released, the brighter the signs.

The symptoms of any insulinoma are due to two opposite processes:

The release of insulin and, as a consequence, acute hypoglycemia.
The production by the body in response to an excess of insulin of its antagonists, hormones-opponents. These are catecholamines - adrenaline, dopamine, norepinephrine.

Cause of symptoms	Time of occurrence	Manifestations
hypoglycemia	Immediately after the insulinoma releases the next portion of insulin.	Feeling of hunger, anger or tearfulness, inappropriate behavior, memory disorders up to amnesia, blurred vision, drowsiness, numbness or tingling, more often in the fingers and toes.
Excess catecholamines	Following hypoglycemia, persists for some time after eating.	Fear, internal trembling, heavy sweating, rapid heartbeat, weakness, headache, feeling of lack of oxygen.
Nervous system damage due to chronic hypoglycemia	Best seen during periods of relative prosperity.	Decreased ability to work, indifference to previously interesting cases, loss of ability for fine work, learning difficulties, erectile dysfunction in men, facial asymmetry, simplification of facial expressions, sore throat.

Most often, attacks are observed in the morning on an empty stomach, after physical exertion or psycho-emotional stress, in women - before menstruation.

Attacks of hypoglycemia are quickly stopped by the intake of glucose, therefore, in the first place, the body reacts to a decrease in sugar with an attack of acute hunger. Most patients unconsciously increase their intake of sugar or sweets and start eating more often. A sudden pathological craving for sweets without other symptoms may be due to a small or inactive insulinoma. As a result of a violation of the diet, weight begins to grow.

A small part of patients behaves in the opposite way - they begin to feel an aversion to food, they lose a lot of weight, and correction of exhaustion has to be included in their treatment plan.

Diagnostic measures

Because of the striking neurological signs, insulinoma is often mistaken for other diseases. Epilepsy, hemorrhages and blood clots in the brain, vegetovascular dystonia, psychoses can be mistakenly diagnosed. A competent doctor, if insulinoma is suspected, conducts several laboratory tests, and then confirms the alleged diagnosis with visual methods.

In healthy people, the lower limit of sugar after an eight-hour fast is 4.1 mmol / l, after a day it drops to 3.3, after three - up to 3 mmol / l, and in women the decrease is slightly greater than in men. In patients with insulinoma, sugar drops to 3.3 already in 10 hours, and a day later acute hypoglycemia with severe symptoms develops.

Based on these data, hypoglycemia provocation is performed to diagnose insulinoma. It is a three-day fast in a hospital, in which only water is allowed. Every 6 hours do an analysis for insulin and glucose. When sugar drops to 3 mmol / l, the periods between analyzes are reduced. The test is terminated when the sugar drops to 2.7 and symptoms of hypoglycemia appear. They are stopped with an injection of glucose. On average, the provocation ends after 14 hours. If the patient survives 3 days without consequences, he has no insulinoma.

The determination of proinsulin is also important in the diagnosis. It is a precursor to insulin produced by beta cells. After leaving them, the proinsulin molecule is cleaved into C-peptide and insulin. Normally, the proportion of proinsulin in the total amount of insulin is less than 22%. With benign insulinoma, this figure is higher than 24%, malignant - more than 40%.

An analysis for C-peptide is performed in patients with suspected mental disorders. This is how cases of insulin administration by injection without a doctor's prescription are calculated. Insulin preparations do not contain C-peptide.

Diagnosis of the location of insulinoma in the pancreas is made using imaging methods, their efficiency is above 90%.

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Can be used:

Angiography is the most efficient method. With its help, an accumulation of vessels that provide blood supply to the tumor is detected. Based on the size of the feeding artery and the network of small vessels, one can judge the location and diameter of the neoplasm.
Endoscopic ultrasonography- allows you to detect 93% of existing tumors.
CT scan- reveals a tumor of the pancreas in 50% of cases.
Ultrasound- effective only in the absence of excess weight.

Treatment

Insulinoma is tried to be removed as early as possible, immediately after diagnosis. All the time before the operation, the patient receives glucose in food or intravenously. If the tumor is malignant, chemotherapy is needed after surgery.

Surgical intervention

Most often, an insulinoma is located on the surface of the pancreas, has clear edges and a characteristic red-brown color, so it is easy to remove without damaging the organ. If the insulinoma inside the pancreas is too small, has an atypical structure, the doctor may not find it during the operation, even if the localization of the tumor was established during the diagnosis. In this case, the intervention is stopped and postponed for some time until the tumor grows and can be removed. At this time, conservative treatment is carried out to prevent hypoglycemia and disorders of nervous activity.

During a second operation, they again seek to detect an insulinoma, and if this fails, a part of the pancreas or liver with a tumor is removed. If the insulinoma is with metastases, it is also necessary to perform a resection of a part of the organ in order to minimize the tumor tissues.

Conservative treatment

Symptomatic treatment of insulinoma in anticipation of surgery is a high-sugar diet. Preference is given to products with, the assimilation of which ensures a uniform supply of glucose into the blood. Episodes of acute hypoglycemia are treated with fast carbohydrates, usually juices with added sugar. If there is severe hypoglycemia with impaired consciousness, the patient is administered glucose intravenously.

If, due to the patient's health condition, the operation is delayed or impossible at all, phenytoin and diazoxide are prescribed. The first drug is an antiepileptic drug, the second is used as a vasodilator in hypertensive crises. These drugs are united by a common side effect -. Using this deficiency for good, you can keep blood glucose at a level close to normal for years. Simultaneously with diazoxide, diuretics are prescribed, as it retains fluid in the tissues.

The activity of small pancreatic tumors can be reduced with verapamil and propranalol, which can inhibit insulin secretion. For the treatment of malignant insulinoma, octreotide is used, it prevents the release of the hormone and significantly improves the patient's condition.

Chemotherapy

Chemotherapy is needed if the tumor is malignant. Streptozocin is used in combination with fluorouracil, 60% of patients are sensitive to them, 50% have a complete remission. The course of treatment lasts 5 days, they will have to be repeated every 6 weeks. The drug has a toxic effect on the liver and kidneys, therefore, in the intervals between courses, drugs are prescribed to support them.

What to expect from the disease

After the operation, the level of insulin quickly decreases, blood glucose rises. If the tumor is detected on time and removed completely, 96% of patients recover. The best outcome is observed in the treatment of small benign tumors. The effectiveness of treatment of malignant insulin is 65%. Relapses occur in 10% of cases.

With small changes in the central nervous system, the body copes on its own, they regress in a few months. Severe nerve damage, organic changes in the brain are irreversible.

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The pancreas is an organ of the endocrine system, the functionality of which determines the process of digestion, as well as the metabolism of glucose in the body. Any pathological processes in the gland are fraught with malfunctions in the digestive tract, as well as the endocrine system. One of the diseases that an organ can undergo is insulinoma.

This is a hormonally active tumor, in most cases benign (85-90%), which originates from β-cells of the islets of Langerhans. Insulinoma itself produces insulin, the excess of which eventually becomes a harbinger of hypoglycemic syndrome. Such formations are more often found after the age of 40 years. Insulinoma can be localized in any part of the pancreas. The presence of this pathology is fraught with the development of dangerous symptoms and consequences, therefore it is important to identify the tumor in a timely manner and remove it.

Causes and mechanism of development

The pancreas synthesizes insulin, which helps to normalize the level. With the formation of insulinoma in the organ, tumor b-cells begin to produce the hormone uncontrollably. That is, the mechanism of regulation of insulin synthesis is violated. This leads to a sharp drop in the level, prerequisites for hypoglycemia are created. In this condition, the release of glucagon, norepinephrine into the blood is activated, which causes adrenergic symptoms.

Based on the nature of insulin, they are divided into:

having a benign nature (ICD code 10 - D13.7);
malignant (ICD code - C25.4).

The exact reasons that give impetus to the formation of insulinoma are not yet known. Many experts suggest that the trigger mechanism of tumor formation lies in disorders of the gastrointestinal tract due to some diseases.

Favorable factors for the growth of prolactinoma can be:

prolonged fasting, which leads to depletion of the body;
anorexia;
enterocolitis;
stomach surgery;
damage to the liver by toxins;
malabsorption of carbohydrates;
renal glucosuria;
deficiency of thyroid hormones;
adrenal insufficiency, with a drop in the level of glucocorticoids;
pituitary dysfunction.

Signs and symptoms

The clinical picture of the pathology is manifested by phases of a latent course and exacerbation of hypoglycemia and reactive hyperadrenalemia. In the absence of attacks, the presence of insulinoma may indicate a strong appetite, which over time can lead to weight gain.

The body reacts to this with characteristic signs:

cold sweat;
tremor;
violation of the heart rhythm;
paresthesia of the limbs;
an attack of epilepsy and loss of consciousness, up to a coma.

Symptoms of a neoplasm in the pancreas may be similar to neurological disorders, which are characterized by:

headache;
lack of coordination;
muscle weakness;
confusion;
hallucinations;
bouts of unreasonable aggression or feelings of euphoria.

After intravenous administration of a glucose solution, the patient's condition returns to normal, but he may not remember the attack. Due to malnutrition of the heart, hypoglycemic syndrome can lead to myocardial infarction. Disorders of the central and peripheral nervous system can manifest themselves even during the latent course of the disease.

Between attacks of hypoglycemia, insulinoma can remind itself of such signs:

blurred vision;
apathy;
decrease in mental abilities;
myalgia.

Symptoms of a tumor in the pancreas are in many ways similar to other diseases (epilepsy, VVD, stroke). This often makes diagnosis difficult, and the patient may be misdiagnosed.

On a note! A pronounced symptom of the tumor is acute hypoglycemia, which develops on an empty stomach as a result of failures in the adaptation mechanisms of the central nervous system. The attack is accompanied by a sharp decrease in glucose to 2.5 mmol / l and below.

Diagnostics

During a visit to a specialist, an anamnesis is first collected. The doctor finds out if the patient has relatives suffering from diseases of the pancreas. It is necessary to determine when and what suspicious symptoms began to appear for the first time.

If hypoglycemia was detected after a blood test, then in order to find out its causes and determine the presence of insulinoma, instrumental studies are prescribed:

The fasting test is a deliberate provocation of hypoglycemia and the Whipple triad characteristic of insulinoma.
Insulin suppression test - the creation of a hypoglycemic state in which the level of C-peptide rises, and sugar drops sharply.
Insulin provocation test - glucose is injected intravenously, as a result of which insulin is released into the blood. In the presence of a tumor, the concentration of the hormone will be significantly higher than normal.

With a positive result of the tests, further instrumental diagnostics are prescribed, which can confirm the presence of insulinoma:

scintigraphy;
angiography;
laparoscopy.

It is necessary to differentiate insulinoma from:

adrenal cancer;
adrenal insufficiency;
dumping syndrome;
medical hypoglycemia.

Effective Treatments

As a rule, in the presence of an insulinoma, its removal is recommended. The volume and complexity of the intervention depend on the location and size of the tumor. A solitary mass that is not deep on the surface of the gland can be excised by enucleation. With multiple insulinomas, as well as large ones, a distal subtotal pancreatectomy is performed. With its ineffectiveness, a total pancreatectomy is done. During the operation, a dynamic determination of the glucose level is carried out.

Complications that may occur after the intervention:

pancreatic necrosis;
abscess of the peritoneum;
peritonitis;
fistulas in the pancreas.

If the tumor is not operable, then conservative therapy is prescribed. Its goal is the prevention of hypoglycemic syndrome. Attacks of hypoglycemia are stopped by the introduction of solutions of glucagon, adrenaline, glucocorticoids. Patients are advised to increase the level of sugar intake of carbohydrate foods.

With persistent hypoglycemia, Diazoxide is treated in combination with a Natriuretic. Other options for drugs that suppress insulin synthesis can be Phenytoin, Varapamil. Malignant insulinomas require courses of chemotherapy with Doxorubicin or Streptozocin.

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recovery prognosis

After removal of the neoplasm, a favorable outcome is observed in 65-80% of cases. The earlier the pathology is detected, the higher the chance of a full recovery. 5-10% of cases of insulinoma are fatal after surgery. Relapses are diagnosed in 3% of patients.

A tenth of insulin degenerates into malignant tumors. Tumor growth can spread by metastases to other organs and systems. The prognosis of survival for 2 years is 60%.

Insulinoma - a tumor in the pancreas that produces insulin, which in the body becomes higher than normal, while the glucose level begins to drop sharply, causing an attack of hypoglycemia. This condition can be extremely dangerous for the health and life of the patient. A thorough examination is needed to determine if insulinoma is the cause of the problem. If it is detected, surgical intervention and further observation of the patient by an endocrinologist and surgeon (if necessary, by an oncologist) are recommended.

Video about the causes of formation, symptoms and methods of treatment of pancreatic insulinoma:

Insulinoma is a tumor of the β-cells of the islets of Langerhans that secretes excessive amounts of insulin, which is manifested by bouts of hypoglycemic symptoms. For the first time, simultaneously and independently of each other, Harris (1924) and V. A. Oppel (1924) described the symptom complex of hyperinsulinism.

In 1927, Wilder et al., while examining tumor extracts from a patient with insulinoma, found that they contained an increased content of insulin. Floyd and co-authors (1964), studying the reaction of the same patients to tolbutamide, glucagon and glucose, noted that they had high levels of insulin in the blood.

In 1929, the first successful operation was performed (Graham) to remove an insulin-producing tumor of the pancreas. It took years of persistent research until the clinical picture of the disease, methods of its diagnosis and surgical treatment acquired a certain definition. In the literature, you can find various terms used to refer to this disease: insuloma, hypoglycemic disease, organic hypoglycemia, relative hypoglycemia, hyperinsulinism, insulin-secreting insuloma. The term "insulinoma" is now generally accepted. According to the reports available in the literature, this neoplasm occurs with the same frequency in both sexes. Data from other researchers indicate that insulinomas occur almost 2 times more often in women.

Insulinoma mainly affects people of the most able-bodied age - 26-55 years. Children rarely suffer from insulinoma.

The pathophysiological basis of the clinical manifestations of tumors from β-cells of the islets of Langerhans is explained by the hormonal activity of these neoplasms. Not obeying the physiological mechanisms that regulate homeostasis in relation to glucose levels, β-cell adenomas lead to the development of chronic hypoglycemia. Since the symptomatology of insulinoma is the result of hyperinsulinemia and hypoglycemia, it becomes clear that the severity of the clinical manifestations of the disease in each individual case indicates the patient's individual sensitivity to insulin and lack of blood sugar. Our observations have shown that patients tolerate a deficiency of glucose in the blood in different ways. The reasons for the extreme polymorphism of symptoms, as well as the predominance of one or another of them in the general symptom complex of the disease in individual patients, are also understandable. Blood glucose is necessary for the vital activity of all organs and tissues of the body, especially the brain. About 20% of all glucose entering the body is spent on brain function. Unlike other organs and tissues of the body, the brain does not have reserves of glucose and does not use free fatty acids as an energy source. Therefore, when the supply of glucose to the cortex of the cerebral hemispheres is stopped for 5-7 minutes, irreversible changes occur in its cells: the most differentiated elements of the cortex die.

Gittler et al distinguished two groups of symptoms that develop with hypoglycemia. The first group includes fainting, weakness, trembling, palpitations, hunger, increased excitability. The author connects the development of these symptoms with reactive hyperadrenalemia. Disorders such as headache, blurred vision, confusion, transient paralysis, ataxia, loss of consciousness, coma are grouped into the second group. With gradually developing symptoms of hypoglycemia, changes associated with the central nervous system (CNS) prevail, and with acute hypoglycemia, symptoms of reactive hyperadrenalemia prevail. The development of acute hypoglycemia in patients with insulinomas is the result of disruption of contra-insular mechanisms and adaptive properties of the CNS.

The clinic and symptomatology of insulinoma is considered by most authors with an emphasis on the manifestations of hypoglycemia attacks, but the study of the symptoms observed in the period between attacks is no less important, since they reflect the damaging effect of chronic hypoglycemia on the central nervous system.

The most characteristic signs of insulinoma are obesity and increased appetite. O. V. Nikolaev (1962) divides the whole variety of symptoms that occur with insulin-producing tumors of the pancreas into manifestations of the latent period and signs of a period of severe hypoglycemia. This concept reflects the phases of relative well-being observed in patients, which are periodically replaced by clinically pronounced manifestations of hypoglycemia.

In 1941, Whipple described the triad of symptoms that most fully combines the various aspects of the clinical manifestations of insulinoma, and also published the results of a study of blood sugar levels at the time of an attack of hypoglycemia.

The occurrence of attacks of spontaneous hypoglycemia on an empty stomach or 2-3 hours after eating.
A drop in blood sugar levels below 50 mg% during an attack.
Relief of an attack by intravenous administration of glucose or sugar intake.

Neuropsychiatric disorders in hyperinsulinism, as well as in insulinoma, occupy a leading place in the latent phase. Neurological symptoms in this disease are insufficiency of the VII and XII pairs of cranial nerves according to the central type, asymmetry of the tendon and periosteal, unevenness or decrease in abdominal reflexes. Pathological reflexes of Babinsky, Rossolimo, Marinescu-Radovich are sometimes observed, and less often others. Some patients have symptoms of pyramidal insufficiency without pathological reflexes. In some patients, sensitivity disorders were detected, which consisted in the appearance of zones of skin hyperalgesia, C3, D4, D12, L2-5. Zakharyin-Ged zones characteristic of the pancreas (D7-9) are observed in single patients. Stem disorders in the form of horizontal nystagmus and upward gaze paresis occur in approximately 15% of patients. Neurological analysis shows that the left hemisphere of the brain is more sensitive to hypoglycemic conditions, which explains the greater frequency of its lesions compared to the right. In the severe course of the disease, symptoms of combined involvement of both hemispheres in the pathological process were observed. In some men, in parallel with the aggravation of the disease, erectile dysfunction developed, especially in patients in whom hypoglycemic conditions occurred almost daily. Our data on neurological disorders in the interictal period in patients with insulinoma were characterized by polymorphism and the absence of any symptoms characteristic of this disease. The degree of these lesions reflects the individual sensitivity of the body's nerve cells to blood glucose levels and indicates the severity of the disease.

Violation of higher nervous activity in the interictal period was expressed in a decrease in memory and mental capacity for work, indifference to the environment, loss of professional skills, which often forced patients to engage in less skilled work, and sometimes led to disability. In severe cases, patients do not remember the events that happened to them, and sometimes they cannot even give their last name and year of birth. The study of the course of the disease showed that the decisive factor in the development of mental disorders is not the duration of the disease, but its severity, which, in turn, depends on the individual sensitivity of the patient to a lack of blood glucose and the severity of compensatory mechanisms.

On the electroencephalograms of patients recorded outside the hypoglycemia attack (on an empty stomach or after breakfast), high-voltage discharges of O-waves, local acute waves and discharges of acute waves were detected, and during an attack of hypoglycemia, along with the described EEG changes, high-voltage slow activity appeared, which in the majority patients at the height of the attack was reflected throughout the recording.

One of the constant symptoms characteristic of insulinoma is the feeling of hunger. So, most of our patients had an increased appetite with a pronounced feeling of hunger before an attack. 50% of them were overweight (from 10 to 80%) due to frequent meals (mainly carbohydrates). It should be emphasized that some patients ate up to 1 kg or more of sugar or sweets per day. In contrast to these observations, some patients experienced aversion to food, required constant care and even intravenous infusion of glucose and protein hydrolysates due to extreme exhaustion.

Thus, neither increased appetite nor hunger can be considered symptoms characteristic of this disease, although they can occur in individual observations. More valuable in a diagnostic sense is the indication of the patient that he constantly has something sweet with him. Most of our patients always had sweets, rich flour products, sugar with them. Some patients, after a certain time, had an aversion to this kind of food, but they could not refuse to take it.

Poor diet gradually led to weight gain and even obesity. However, not all patients had an excess of body weight, in some of them it was normal and even below normal. We observed weight loss more often in persons with reduced appetite, as well as in patients who have an aversion to food.

In some patients, muscle pains could be noted, which many authors associate with the development of various degenerative processes in muscle tissue and its replacement with connective tissue.

Little awareness of doctors about this disease often leads to diagnostic errors - and patients with insulinoma are treated for a long time and unsuccessfully for a wide variety of diseases. More than half of the patients are misdiagnosed.

Diagnosis of insulinoma

When examining such patients from the anamnesis, the time of the onset of the attack, its connection with food intake, is clarified. The development of a hypoglycemic attack in the morning, as well as when skipping the next meal, with physical and mental stress, in women on the eve of menstruation, testifies in favor of insulinoma. Physical research methods in the diagnosis of insulinoma do not play a significant role due to the small size of the tumor.

Great importance in the diagnosis of insulinoma is given to the conduct of functional diagnostic tests.

In the study of blood sugar levels on an empty stomach before treatment, it was found to decrease below 60 mg% in the vast majority of patients. It should be noted that in the same patient on different days the blood sugar level varied and could be normal. When determining the level of insulin in the blood serum on an empty stomach, the vast majority showed an increase in its content, however, in some cases, during repeated studies, its normal values were also observed. Such fluctuations in blood sugar and insulin levels on an empty stomach, apparently, can be associated with the unequal hormonal activity of insulinoma on different days, as well as with the heterogeneous severity of contra-insular mechanisms.

Summarizing the results of studies obtained in patients with insulinomas during tests with fasting, leucine, tolbutamide and glucose, we can conclude that the most valuable and accessible diagnostic test for insulinomas is the test with fasting, which in all patients was accompanied by the development of an attack of hypoglycemia with a sharp decrease in blood sugar levels, although the level of insulin during this test often remains unchanged compared to its value before the attack. A test with leucine and tolbutamide in patients with insulinomas leads to a pronounced increase in serum insulin levels and a significant decrease in blood sugar levels with the development of an attack of hypoglycemia, but these tests do not give positive results in all patients. Glucose loading is less diagnostically indicative, although it has a certain significance when compared with other functional tests and the clinical picture of the disease.

As our studies have shown, not in all cases where the diagnosis of insulinoma can be considered proven, there are elevated insulin values.

Recent studies have shown that indicators of proinsulin and C-peptide secretion are more valuable in diagnosing insulinoma, and the values of immunoreactive insulin (IRI) are usually assessed simultaneously with the level of glycemia.

The ratio of insulin to glucose is determined. In healthy people, it is always below 0.4, while in most patients with insulinomas, it exceeds this figure and often reaches 1.

Recently, great diagnostic value has been attached to the C-peptide suppression test. Within 1 hour, the patient is injected intravenously with insulin at the rate of 0.1 U/kg. With a decrease in C-peptide by less than 50%, the presence of insulinoma can be assumed.

The vast majority of insulin-producing tumors of the pancreas do not exceed 0.5-2 cm in diameter, which makes it difficult to detect them during surgery. So, in 20% of patients during the first, and sometimes the second, and the third operation, the tumor cannot be detected.

Malignant insulinomas, one third of which metastasize, occur in 10-15% of cases. For the purpose of topical insulin diagnosis, three methods are mainly used: angiographic, portal system catheterization and computed tomography of the pancreas.

Angiographic diagnosis with insulin is based on the hypervascularization of these neoplasms and their metastases. The arterial phase of the tumor is represented by the presence of a hypertrophied artery supplying the tumor and a thin network of vessels in the area of the lesion. The capillary phase is characterized by a local accumulation of a contrast agent in the area of the neoplasm. The venous phase is manifested by the presence of a tumor-draining vein. Most often, insulinoma is found at the capillary stage. The angiographic research method makes it possible to diagnose a tumor in 60-90% of cases. The greatest difficulties arise with small tumor sizes, up to 1 cm in diameter, and with their localization in the head of the pancreas.

Difficulties in insulin localization and their small size make it difficult to detect them using computed tomography. Such tumors, located in the thickness of the pancreas, do not change its configuration, and in terms of the X-ray absorption coefficient do not differ from the normal tissue of the gland, which makes them negative. The reliability of the method is 50-60%. In some cases, they resort to catheterization of the portal system in order to determine the level of IRI in the veins of various parts of the pancreas. According to the maximum value of IRI, one can judge the localization of a functioning neoplasm. This method, due to technical difficulties, is usually used with negative results obtained from previous studies.

Sonography in the diagnosis of insulin is not widely used due to overweight in the vast majority of patients, since the fat layer is a significant obstacle to the ultrasound wave.

It should be noted that topical diagnostics using modern research methods in 80-95% of patients with insulinomas makes it possible to establish the localization, size, prevalence and determine the malignancy (metastases) of the tumor process before surgery.

Differential diagnosis of insulinoma is carried out with non-pancreatic tumors (tumors of the liver, adrenal glands, various mesenchymomas). In all these conditions, hypoglycemia is observed. Non-pancreatic tumors differ from insulin in their size: as a rule, they are large (1000-2000 g). Tumors of the liver, adrenal cortex and various mesenchymomas have such dimensions. Neoplasms of this size are easily detected by physical examination methods or conventional radiological ones.

Great difficulties arise in the diagnosis of insulinoma with the hidden exogenous use of insulin preparations. The main evidence of exogenous use of insulin is the presence of antibodies to insulin in the patient's blood, as well as a low content of C-peptide with a high level of total IRI. Endogenous secretion of insulin and C-peptide is always in equimolar ratios.

A special place in the differential diagnosis of insulinoma is occupied by hypoglycemia in children, due to the total transformation of the ductal epithelium of the pancreas into b-cells. This phenomenon is called nesidioblastosis. The latter can only be established morphologically. Clinically, it is manifested by severe, difficult-to-correct hypoglycemia, which forces urgent measures to be taken to reduce the mass of pancreatic tissue. The generally accepted volume of the operation is resection of the gland by 80-95%.

Treatment of insulinoma

Conservative therapy for insulinoma includes the relief and prevention of hypoglycemic conditions and the impact on the tumor process through the use of various hyperglycemic agents, as well as more frequent meals for the patient. Traditional hyperglycemic drugs include epinephrine (epinephrine) and norepinephrine, glucagon (glucagen 1 mg hypokit), glucocorticoids. However, they give a short-term effect, and the parenteral route of administration of most of them limits their use. Thus, the hyperglycemic effect of glucocorticoids is manifested with the use of large doses of drugs that cause cushingoid manifestations. Some authors note a positive effect on glycemia of diphenylhydantoin (difenin) at a dose of 400 mg / day, as well as diazoxide (hyperstat, proglycem). The hyperglycemic effect of this non-diuretic benzothiazide is based on the inhibition of insulin secretion from tumor cells. The drug is used at a dose of 100-600 mg / day in 3-4 doses. Available in capsules of 50 and 100 mg. The drug, due to its pronounced hyperglycemic effect, is able to maintain a normal level of glucose in the blood for years. It has the ability to retain water in the body by reducing the excretion of sodium and leads to the development of edematous syndrome. Therefore, the intake of diazoxide must be combined with diuretics.

In patients with malignant metastatic tumors of the pancreas, the chemotherapeutic drug streptozotocin has been successfully used (L. E. Broder, S. K. Carter, 1973). Its action is based on the selective destruction of pancreatic islet cells. 60% of patients are sensitive to the drug to some extent.

An objective decrease in the size of the tumor and its metastases was noted in half of the patients. The drug is administered intravenously by infusion. Applied doses - daily up to 2 g, and course up to 30 g, daily or weekly. Side effects of streptozotocin are nausea, vomiting, nephro- and hepatotoxicity, diarrhea, hypochromic anemia. In the absence of tumor sensitivity to streptozotocin, doxorubicin (adriamycin, adriablastin, rastocin) can be used (R. C. Eastman et al., 1977).

The anatomical features of the pancreas, located in a hard-to-reach area, in close proximity to a number of vital organs, its increased sensitivity to surgical trauma, the digestive properties of the juice, its proximity to extensive nerve plexuses, and its connection with reflexogenic zones, significantly complicate the performance of surgical operations on this organ and complicate relief of the subsequent wound process. In connection with the anatomical and physiological features of the pancreas, the issues of reducing operational risk are of paramount importance. Reducing the risk of surgical intervention is achieved through appropriate preoperative preparation, choosing the most rational method of anesthesia, achieving minimal trauma during the search and removal of the tumor, and carrying out preventive and therapeutic measures in the postoperative period.

Thus, according to our data, the level of insulin in the blood of the vast majority of patients with insulinomas is elevated, while the blood sugar level is reduced. Hypoglycemic attacks during the test with fasting occurred from 7 to 50 hours from the moment of fasting, in most patients after 12-24 hours.

Oral intake of leucine at a dose of 0.2 g per 1 kg of body weight in almost all patients was accompanied by an increase in insulin levels and a sharp decrease in blood sugar levels 30-60 minutes after taking the drug with the development of an attack of hypoglycemia.

Intravenous administration of tolbutamide in the vast majority of patients caused a pronounced increase in blood insulin and a decrease in sugar content with the development of an attack of hypoglycemia after 30-120 minutes from the start of the test.

Comparison of diagnostic tests in patients with insulinomas showed the greatest value of the test with fasting.

In the case of a recurrence of the disease in the postoperative period, the change in blood sugar and insulin levels during tests with fasting, leucine, tolbutamide was the same as before surgery.

Comparison of the data of electroencephalographic studies conducted before and after surgical treatment showed that in some patients with a longer duration of the disease and frequently recurring episodes of hypoglycemia, irreversible organic changes in the brain remained. With early diagnosis and timely surgical treatment, changes in the central nervous system disappear, as evidenced by the data of EEG studies.

The follow-up analysis indicates the high efficiency of the surgical method of treatment with insulin and the relative rarity of relapses of these neoplasms after their removal. In 45 (80.3%) of 56 patients, clinical recovery occurred after removal of the insulinoma.

The main radical method of treatment with insulin is surgical. Conservative therapy is prescribed for inoperable patients, in case of refusal of the patient from surgery, as well as in case of unsuccessful attempts to detect a tumor during surgery.

R. A. Manusharova, doctor of medical sciences, professor
RMAPO, Moscow

For literature inquiries, please contact the editor.

Diagnosis consists of a 48- or 72-hour fast test with measurements of glucose and insulin levels, followed by endoscopic ultrasound. Treatment - surgical (if possible).

Among all cases of insulinoma, 80% have a single node and, if detected, a cure can be achieved. 10% insulin malignant. Insulinomas develop at a rate of 1/250,000. Insulinomas in type I MEN are more likely to be multiple.

Hidden administration of exogenous insulin can provoke episodes of hypoglycemia, resembling the picture of insulinoma.

Prevalence of pancreatic insulinoma

The overall incidence of insulin is low - 1-2 cases per 1 million population per year, but they account for almost 80% of all known hormonally active pancreatic neoplasms. They can be either solitary (usually sporadic forms) or multiple (more often hereditary), which creates diagnostic difficulties before surgery. Insulinomas are localized in the pancreas, but in 1-2% of cases they can develop from ectopic tissue and have extrapancreagic localization.

Insulinoma is a frequent component of the MEN type I syndrome, which also includes hormonally active tumors of the parathyroid glands, adenohypophysis, and tumors of the adrenal cortex (often hormonally inactive).

In most patients, insulinoma is benign, in 10-20% it has signs of malignant growth. Insulinomas larger than 2-3 cm in diameter are often malignant.

Classification of pancreatic insulinoma

In ICD-10 insulinoma corresponds to the following headings.

C25.4 Malignant neoplasm of pancreatic islet cells.
D13.7 Benign neoplasm of pancreatic islet cells.

Insulinoma is the most common cause of the syndrome of organic hyperinsulinism, which is characterized by severe HS, mainly at night and on an empty stomach, i.e. after a long enough fast. Hyperinsulinism is an endogenous hyperproduction of insulin, which leads to an increase in its concentration in the blood (hyperinsulinemia) with a high probability of developing a symptom complex of hypoglycemia. Organic hyperinsulinism is formed on the basis of morphological structures that produce large amounts of insulin. In addition to insulinoma, more rare causes of organic hyperinsulinism are adenomatosis and islet cell hyperplasia - nesidioblastosis.

Based on practical purposes, a functional form of hyperinsulinism is distinguished, in most cases characterized by a more benign course and prognosis (Table 3.21).

Causes and pathogenesis of pancreatic insulinoma

Under conditions of hyperinsulinemia, the formation and fixation of glycogen in the liver and muscles increases. Insufficient supply of the brain with the main energy substrate is initially accompanied by functional neurological disorders, and then by irreversible morphological changes in the central nervous system with the development of cerebroasthenia and a decrease in intelligence.

In the absence of timely food intake, attacks of hypoglycemia of varying severity develop, manifested by adrenergic and cholinergic symptoms and symptoms of neuroglycopenia. The result of a long-term severe energy deficiency of the cells of the cerebral cortex is their edema and the development of hypoglycemic coma.

The main causes of functional hyperinsulinism in adults

The reasons	Mechanisms of hyperinsulinemia
Conditions after surgical interventions on the stomach, dumping syndrome	Violation of the physiology (acceleration) of the passage of food through the gastrointestinal tract, increased production of GLP-1 - an endogenous stimulator of insulin secretion
The initial stages of SD	Severe compensatory hyperinsulinemia due to insulin resistance
Glucose stimulated hypoglycemia	Anomalies of parietal digestion with a high rate of absorption of food substrates, which does not correspond to the normal process of insulin secretion. Decreased sensitivity of P-cells to glucose with a delay and subsequent inadequate compensatory increase in insulin secretion
Autonomic dysfunction	Increased vagus tone and functionally determined hypermotility of the gastrointestinal tract with an accelerated passage of food
Autoimmune hypoglycemia	Accumulation of insulin-antibody complexes to insulin in high concentrations and periodic release of free insulin from them
Overdose of drugs - stimulants of insulin secretion (PSM, glinides)	Direct stimulation of secretion by P-cells of the pancreas
Chronic renal failure	Decreased formation of insulinase in the kidneys and degradation of endogenous insulin

Symptoms and signs of pancreatic insulinoma

Hypoglycemia in insulinoma develops on an empty stomach. Symptoms may be blurred and sometimes mimic various psychiatric and neurological disorders. Often there are symptoms of increased sympathetic activity (general weakness, trembling, palpitations, sweating, hunger, irritability).

The absence of specific symptoms is one of the main reasons for the late diagnosis of insulinoma. In this case, the anamnesis of the disease can be calculated for years. Of the variety of clinical manifestations, psycho-neurological symptoms stand out especially - episodes of disorientation, speech and motor disorders, strange behavior, decreased mental capacity for work and memory, loss of professional skills, amnesia, etc. The vast majority of other symptoms (including cardiovascular and gastrointestinal) are a manifestation of acutely developed neuroglycopenia and autonomic response.

Often, patients wake up with difficulty, are disoriented for a long time, answer the simplest questions in monosyllables, or simply do not come into contact with others. Attention is drawn to the confusion or slurring of speech, the same type of repetitive words and phrases, unnecessary monotonous movements. The patient may be disturbed by headache and dizziness, paresthesia of the lips, diplopia, sweating, a feeling of internal trembling or chills. Episodes of psychomotor agitation and epileptiform seizures are possible. There may be symptoms such as a feeling of hunger and emptiness in the stomach associated with the reaction of the gastrointestinal system.

As the pathological process deepens, stupor, hand tremors, muscle twitches, convulsions appear, and coma may develop. Due to retrograde amnesia, patients, as a rule, cannot tell about the nature of the attack.

Due to the need for frequent eating, patients often become obese.

With an increase in the duration of the disease, the condition of patients in the interictal period changes significantly due to violations of the higher cortical functions of the central nervous system: changes in the intellectual and behavioral spheres develop, memory deteriorates, mental work capacity decreases, professional skills are gradually lost, negativism and aggression may develop, which is associated with characterological features person.

Diagnosis of pancreatic insulinoma

content of insulin.
In some cases - the content of C-peptide and proinsulin.
Endoscopic ultrasound.

With the development of symptoms, it is necessary to evaluate the level of glucose in the blood serum. In the presence of hypoglycemia, it is necessary to evaluate the level of insulin in a simultaneously taken blood sample. Hyperinsulinemia > 6 μU/ml indicates the presence of insulin-mediated hypoglycemia.

Insulin is secreted in the form of proinsulin, consisting of an α-chain and a β-chain connected by a C-peptide. Because commercially produced insulin contains only β-chain, clandestine administration of insulin preparations can be detected by measuring the level of C-peptide and proinsulin. With the secret use of insulin preparations, the level of these indicators is normal or reduced.

Since many patients have no symptoms at the time of examination (and therefore no hypoglycemia), hospitalization is indicated for a 48-72 hour fasting test to confirm the diagnosis. Almost all patients with insulinoma (98%) within a 48-hour fasting develop clinical manifestations; in 70-80% - within the next 24 hours. The role of hypoglycemia in the onset of symptoms is confirmed by the Whipple triad:

symptoms appear on an empty stomach;
symptoms appear with hypoglycemia;
eating carbohydrates leads to a reduction in symptoms.

If components of the Whipple triad are not observed after a fasting period, and plasma glucose levels after an overnight fasting period are > 50 mg/dL, a C-peptide suppression test can be performed. During insulin infusion in patients with insulinoma, there is no decrease in the content of C-peptide to a normal level.

Endoscopic ultrasonography has a sensitivity of >90% in detecting a tumor focus. For this purpose, PET is also performed. CT has no proven informative value; in carrying out arteriography or selective catheterization of the portal and splenic veins, as a rule, there is no need.

Despite the vivid clinical picture, with organic hyperinsulinism, diagnoses such as cerebrovascular accident, diencephalic syndrome, epilepsy, and alcohol intoxication are often established.

With a fasting blood glucose concentration of more than 3.8 mmol / l and the absence of convincing data for HC in the anamnesis, the diagnosis of insulinoma can be excluded. With fasting glycemia of 2.8-3.8 mmol / l, as well as more than 3.8 mmol / l in combination with a history of hypoglycemia, a fasting test is performed, which is a method of provocation of the Whipple triad. The sample is considered positive when laboratory changes and clinical symptoms of hypoglycemia appear, which are stopped by intravenous administration of a glucose solution. In most patients, the Whipple triad is provoked within a few hours from the start of the test. In organic hyperinsulinism, the levels of insulin and C-peptide are stably elevated and do not decrease during fasting, in contrast to healthy individuals and patients with functional hyperinsulinism.

With a positive fasting test, topical tumor diagnosis is performed using ultrasound (including endoscopic ultrasound of the gastrointestinal tract with visualization of the pancreas), MRI, CT, selective angiography, percutaneous transhepatic catheterization of the portal vein branches, pancreaticoscopy with biopsy.

Up to 90% of insulins have somatostatin receptors. Somatostatin receptor scintigraphy using the radioactive synthetic drug somatostatin - pentetreotide allows for topical diagnosis of tumors and their metastases, as well as postoperative control over the radicalness of surgical treatment.

An important diagnostic method is intraoperative revision of the pancreas and liver, which makes it possible to detect a neoplasm and metastases that could not be detected before the operation.

Differential Diagnosis

If, after laboratory confirmation of organic hyperinsulinism, it was not possible to visualize insulinoma, a percutaneous or laparoscopic diagnostic needle biopsy of the pancreas is performed. Subsequent morphological examination allows us to establish other causes of organic hyperinsulinism - nesidioblastosis, pancreatic microadenomatosis. In the course of differential diagnosis, a number of diseases and conditions accompanied by the development of hypoglycemia should be excluded: starvation; severe violations of the liver, kidneys, sepsis (due to a decrease in gluconeogenesis or a decrease in the metabolism of endogenous insulin); large mesenchymal tumors utilizing glucose; adrenal insufficiency and severe hypothyroidism; the introduction of an excess amount of insulin in the treatment of diabetes, the use of significant amounts of alcohol and large doses of certain drugs; congenital disorders of glucose metabolism (defects in gluconeogenesis enzymes); formation of antibodies to insulin.

Treatment of pancreatic insulinoma

Education resection.
Diazoxide and sometimes octreotide to correct hypoglycemia.

The frequency of complete cure in surgical treatment reaches 90%. A solitary small insulinoma on or just below the surface of the pancreas can usually be removed by enucleation. With a single large or deep adenoma, with multiple formations of the body and / or tail, or if insulinoma cannot be detected (this is a rare case), a distal subtotal pancreatectomy is performed. In less than 1% of cases, insulinoma has an ectopic location in the peripancreatic tissues - in the wall of the duodenum, periduodenal region and can only be detected with a thorough surgical revision. Pancreatoduodenectomy (Whipple operation) is performed for resectable malignant insulinomas of the proximal pancreas. Total pancreatectomy is performed in cases where a previous subtotal pancreatectomy has failed.

With long-term hypoglycemia, diazoxide can be given in combination with a natriuretic. The somatostatin analog octreotide has a variable effect and may be considered in patients with long-term hypoglycemia not responding to diazoxide treatment. Against the background of the use of octreotide, it may be necessary to additionally take pancreatin preparations, because. pancreatic secretion is suppressed. Other drugs with moderate and variable inhibitory effects on insulin secretion include verapamil, diltiazem, and phenytoin.

If symptoms cannot be controlled, trial chemotherapy can be given, but its effectiveness is limited. When prescribing streptozocin, the probability of achieving an effect is 30-40%, in combination with 5-fluorouracil - 60% (remission duration up to 2 years). Other treatments are doxorubicin, chlorozotocin, interferon.

The most radical and optimal method of treatment is surgical enucleation of the tumor or partial resection of the pancreas. In malignant insulinoma, pancreatic resection is combined with lymphadenectomy and removal of visible regional metastases (often in the liver).

If it is impossible to remove the tumor and if surgical treatment is ineffective, symptomatic therapy is carried out aimed at prevention (frequent fractional intake of carbohydrate foods, diazoxide) and relief of GS (intravenous administration of glucose or glucagon).

If during the examination positive scan results with octreotide were obtained, then synthetic analogues of somatostatin are prescribed - octreotide and its forms of prolonged action [octreotide (octreotide-depot), lanreotide], which have antiproliferative activity and inhibit not only the secretion of growth hormone, but also insulin, serotonin, gastrin, glucagon, secretin, motilin, vasointestinal polypeptide, pancreatic polypeptide.

When confirming the malignant nature of insulinoma, chemotherapy with streptozotocin is indicated, the action of which is the selective destruction of P-cells of the pancreas.

Dispensary observation

Patients are monitored by an endocrinologist and a surgeon, if necessary, together with an oncologist. After surgical treatment, an annual hormonal examination, ultrasound of the liver, if indicated, MRI and MRI of the abdominal organs are performed to exclude recurrence and metastasis.

Prevention of pancreatic insulinoma

It is necessary to prevent HS, which is carried out by individually more frequent intake of carbohydrate foods.

Prognosis of pancreatic insulinoma

With timely radical treatment of benign insulinoma, the prognosis is favorable.