Insulinoma

Insulinoma is the most common endocrine tumor of the pancreas. It accounts for 70-75% of hormonally active tumors of this organ. Insulinoma can be solitary and multiple, in 1-5% of cases the tumor is a component of multiple endocrine adenomatosis. It can occur at any age, but most often in people 40-60 years old, with equal frequency in men and women. Benign tumors predominate (approximately 90% of cases). Insulinoma can be localized in any part of the pancreas. In about 1% of patients, it is located extrapancreatically - in the omentum, wall of the stomach, duodenum, hilum of the spleen and other areas. Tumor sizes vary from a few millimeters to 15 cm in diameter, most often making up 1-2 cm.

The bulk of the 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 metastasize to various organs, but most often to the liver.

The main pathogenetic factors in insulinoma are uncontrolled production and secretion of insulin, regardless of the blood glucose level (with increased production of insulin by tumor cells, their ability to deposit propeptide and peptide is reduced).Hypoglycemia resulting from hyperinsulinism causes most of the clinical symptoms.

Along with insulin, insulinoma cells can also produce other peptides in increased quantities - glucagon, PP.

Insulinoma is a tumor of the beta cells of the islets of Langerhans that secretes excess insulin, which is manifested by a hypoglycemic symptom complex. The following names for this disease can be found in the literature: insuloma, hypoglycemic disease, organic hypoglycemia, Harris syndrome, organic hyperinsulinism, insulin-secreting apudoma. The currently generally accepted term is insulinoma.

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Epidemiology

Insulin-secreting tumor is described in all age groups - from newborns to the elderly, but most often it affects the most able-bodied - from 30 to 55 years old. Among the total number of patients, children make up about 5%.

Causes insulinomas

Soon after Banting and West discovered insulin in 1921, symptoms of its overdose in clinical use of commercial preparations in patients with diabetes mellitus became known. This allowed Harris to formulate the concept of spontaneous hypoglycemia caused by increased secretion of this hormone. Numerous attempts to identify and treat with insulin were made in 1929, when Graham first succeeded in successfully removing an insulin-secreting tumor. Since then, there have been reports in the world literature of approximately 2,000 patients with functioning beta-cell neoplasms.

There is no doubt that the symptoms of insulinoma are related to its hormonal activity. Hyperinsulinism is the main pathogenetic mechanism on which the entire symptom complex of the disease depends. Constant secretion of insulin, not obeying the physiological mechanisms regulating homeostasis in relation to glucose, leads to the development of hypoglycemia, blood glucose is necessary for the normal functioning of all organs and tissues, especially the brain, the cortex of which uses it more intensively than all other organs. About 20% of all glucose entering the body is spent on brain function. The special sensitivity of the brain to hypoglycemia is explained by the fact that, unlike almost all tissues of the body, the brain does not have carbohydrate reserves and is not able to use circulating free fatty acids as an energy source. When glucose stops entering the cerebral cortex for 5-7 minutes, irreversible changes occur in its cells, and the most differentiated elements of the cortex die.

When the glucose level decreases to hypoglycemia, mechanisms aimed at glycogenolysis, gluconeogenesis, mobilization of free fatty acids, and ketogenesis are activated. These mechanisms mainly involve 4 hormones - norepinephrine, glucagon, cortisol, and growth hormone. Apparently, only the first of them causes clinical manifestations. If the reaction to hypoglycemia with the release of norepinephrine occurs quickly, the patient experiences weakness, tremor, tachycardia, sweating, anxiety, and a feeling of hunger; symptoms from the central nervous system include dizziness, headache, double vision, behavioral disturbances, and loss of consciousness. When hypoglycemia develops gradually, changes associated with the central nervous system prevail, and the reactive (to norepinephrine) phase may be absent.

Symptoms insulinomas

Symptoms of insulinoma usually include both groups of symptoms to varying degrees, but the presence of neuropsychiatric disorders and low awareness of 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. Mistaken diagnoses are made in % of patients with insulinoma.

Symptoms of insulinoma are usually 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 of insufficiency of the VII and XII pairs of cranial nerves of the central type; asymmetry of tendon and periosteal reflexes. Sometimes pathological reflexes of Babinsky, Rossolimo, Marinescu-Radovic can be detected. In some patients, symptoms of pyramidal insufficiency without pathological reflexes are noted. Impairment of higher nervous activity in the interictal period is expressed in a decrease in memory and mental performance, loss of professional skills, which often forces patients to engage in less skilled work.

Misdiagnoses in patients with insulinoma

Diagnosis	%
Epilepsy	34
Brain tumor	15
Cerebral circulatory disorder	15
Vegetative-vascular dystonia	11
Diencephalic syndrome	9
Psychosis	5
Residual effects of neuroinfection	3
Neurasthenia	3
Intoxication	2
Poisoning and others	3

The period of acute hypoglycemia is the result of the failure of counterinsular factors and 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 food intake. Usually, patients cannot "wake up". This is no longer sleep, but a disorder of consciousness of varying depth, replacing it. For a long time, they remain disoriented, make unnecessary repetitive movements, and answer simple questions in monosyllables. The epileptiform seizures observed in these patients differ from true ones in their longer duration, choreoform convulsive twitching, hyperkinesis, and abundant neurovegetative symptoms. Despite the long course of the disease, patients do not experience the characterological personality changes described in epileptics.

Hypoglycemic conditions in patients with insulinoma often manifest themselves in attacks of psychomotor agitation: some rush about, shout something, threaten someone; others sing, dance, answer questions irrelevantly, give the impression of being drunk. Sometimes hypoglycemia in insulinoma can manifest itself in a dream-like state: patients leave or go in an unspecified direction and then cannot explain how they ended up there. Some commit antisocial acts - they relieve themselves at the first need, enter into various unmotivated conflicts, can pay with any objects instead of money. The progression of the attack most often ends in a profound disorder of consciousness, from which patients are brought out by intravenous infusion of glucose solution. If assistance is not provided, then the hypoglycemic attack can last from several hours to several days. Patients cannot describe the nature of the attack, since they do not remember what happened - retrograde amnesia.

Hypoglycemia due to insulinoma occurs on an empty stomach. Symptoms are insidious and may resemble various psychiatric and neurological disorders. CNS disturbances include headache, confusion, hallucinations, muscle weakness, paralysis, ataxia, personality changes, and possibly, with progression, loss of consciousness, seizure, and coma. Autonomic symptoms ( dizziness, weakness, tremor, palpitations, sweating, hunger, increased appetite, nervousness) are often absent.

For more details, read the article: Symptoms of insulinoma

Diagnostics insulinomas

Functional tests are used in the diagnostics of insulinoma. A widely used test is a 24-hour fasting test with a low-calorie diet (with limited carbohydrates and fats) for 72 hours. Patients with insulinoma develop symptoms of hypoglycemia, but even in their absence, the blood glucose concentration is recorded below 2.77 mmol/l during the day. Insulinoma cells autonomously produce insulin regardless of the blood glucose level, and the insulin/glucose ratio is high (due to a decrease in glucose and an increase in insulin levels), which is pathognomonic. The diagnostic accuracy of the fasting test is almost 100%.

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

The insulin provocation test is aimed at releasing endogenous insulin by intravenous administration of glucose (0.5 g/kg) or glucagon (1 mg) or hypoglycemic sulfonylurea derivatives (e.g., tolbutamide at a dose of 1 g). However, 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 increases significantly with the simultaneous administration of glucose and calcium (5 mg/kg). Insulinoma cells are more sensitive to calcium stimulation than normal B cells. In addition, this test compensates for the development of hypoglycemia with glucose infusion.

Along with the determination of fasting serum glucose, insulin and C-peptide, radioimmune proinsulin testing can help diagnose insulinoma. However, hyperproinsulinemia is possible not only in patients with organic hyperinsulinism, but also in patients with uremia, liver cirrhosis, thyrotoxicosis, and in individuals who have taken insulin or hypoglycemic drugs, for example, for suicidal purposes.

For more details, read the article: Diagnosis of insulinoma

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Differential diagnosis

Differentiate spontaneous hypoglycemia from extrapancreatic diseases without hyperinsulinism: from pituitary and/or adrenal insufficiency, severe liver damage (insufficient glucose production), extrapancreatic malignant tumors, such as large fibrosarcoma (increased glucose consumption), galactosemia and glycogen storage diseases (enzyme deficiency), from CNS diseases (insufficient carbohydrate consumption). Diagnosis is aided by clinical and laboratory data specific to each of the above groups of diseases. To differentiate them from insulinoma, fasting immunoreactive insulin and C-peptide levels are measured along with glucose levels and a glucose andcalcium challenge test. Hyperinsulinemia and a positive insulin challenge test will indicate insulinoma. Fasting and hypocaloric diet tests are contraindicated in some cases (for example, in primary or secondary hypocorticism).

It is necessary to conduct differential diagnostics between organic hypoglycemia and toxic (alcoholic, as well as drug-induced, caused by the introduction of insulin or hypoglycemic sulfonylurea derivatives). Alcoholic hypoglycemia occurs without hyperinsulinemia. The introduction of exogenous insulin or hypoglycemic drugs leads to an increased content of immunoreactive insulin in the blood with a normal or decreased level of C-peptide, since both peptides are formed in equimolar quantities from proinsulin and enter the bloodstream.

In reactive (postprandial) forms of hyperinsulinism - increased vagus nerve tone, pre-diabetes mellitus, late dumping syndrome - the fasting blood glucose level is normal.

In newborns and small children, hyperplasia of islet cells, nesidioblastosis, is occasionally encountered, which can be the cause of organic hypoglycemia (nesidioblasts are epithelial cells of small pancreatic ducts that differentiate into insulin-competent cells). In small children, nesidioblastosis is indistinguishable from insulinoma based on clinical and laboratory data.

Treatment insulinomas

In general, the effectiveness of surgical treatment of insulinoma reaches 90%. The operative mortality rate is 5-10%. Small solitary superficial insulinomas of the pancreas are usually enucleated surgically. If the adenoma is solitary but large and localized deep in the tissue of the body or tail of the gland, if multiple formations of the body or tail (or both) are detected, if insulinoma is not detected (an atypical circumstance), distal, subtotal pancreatectomy is performed. In less than 1% of cases, ectopic localization of insulinoma is observed, located 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 thorough search during surgery. In case of proximal localization of malignant operable insulinomas, pancreaticoduodenectomy (Whipple operation) is indicated. Total pancreatectomy is performed when subtotal pancreatectomy is ineffective.

If hypoglycemia persists, diazoxide may be used, starting with an initial dose of 1.5 mg/kg orally twice daily, together with a natriuretic. The dose may be increased to 4 mg/kg. The somatostatin analogue octreotide (100-500 mcg subcutaneously 2-3 times daily) is not always effective and should be considered in patients with ongoing hypoglycemia refractory to diazoxide. Patients who respond to octreotide may be given the drug intramuscularly at 20-30 mg once daily. Patients receiving octreotide should also be given pancreatic enzymes because octreotide inhibits pancreatic enzyme secretion. Other drugs that have a small and variable effect on insulin secretion include verapamil, diltiazem, and phenytoin.

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

For more details, read the article: Treatment of insulinoma