Non-diabetes mellitus

Non-diabetes mellitus is a disease characterized by diabetes, an increase in plasma osmolarity, arousing the thirst mechanism, and compensatory consumption of a large amount of fluid.

[1], [2], [3], [4], [5],

Epidemiology

The frequency of diabetes insipidus is not specified. Point to 0.5-0.7% of the total number of patients with endocrine pathology. The disease occurs in equal measure in people of both sexes at any age, but more often in 20-40 years. Congenital forms may be present in children from the first months of life, but sometimes they are detected much later.

[6], [7], [8], [9], [10], [11], [12]

Causes of the diabetes insipidus

Non-diabetes mellitus is caused by a deficiency of vasopressin controlling the reabsorption of water in the distal tubules of the renal nephron, where under physiological conditions a negative clearance of "free" water is provided on a scale necessary for homeostasis, and the urine concentration is completed.

There are a number of etiological classifications of diabetes insipidus. More often, the division into central (neurogenic, hypothalamic) diabetes insipidus with insufficient production of vasopressin (complete or partial) and peripheral is used. The central forms include true, symptomatic and idiopathic (familial or acquired) diabetes insipidus. With peripheral diabetes insipidus, the normal production of vasopressin remains, but the sensitivity to the hormone of the renal tubular receptors (nephrogenic vasopressin-resistant diabetes insipidus) or vasopressin is intensively inactivated in the liver, kidneys, placenta.

The cause of central forms of diabetes insipidus can be inflammatory, degenerative, traumatic, tumor, etc. Lesions of various parts of the hypothalamic-neurohypophysis system (anterior nuclei of the hypothalamus, supraopticogygophoreal tract, posterior lobe of the pituitary gland). The specific causes of the disease are very diverse. True diabetes insipidus is preceded by a number of acute and chronic infections and diseases: influenza, meningoencephalitis (diencephalitis), tonsillitis, scarlet fever, whooping cough, all kinds of typhus, septic conditions, tuberculosis, syphilis, malaria, brucellosis, rheumatism. Influenza with its neurotropic influence is more common than other infections. As the overall incidence of tuberculosis, syphilis and other chronic infections decreases, their causative role in the onset of diabetes insipidus has significantly decreased. The disease can occur after craniocerebral (accidental or surgical), mental trauma, electric shock, hypothermia, during pregnancy, soon after childbirth, abortion.

The cause of diabetes insipidus in children may be birth trauma. Symptomatic diabetes insipidus is caused by a primary and metastatic tumor of the hypothalamus and pituitary gland, adenoma, teratoma, glioma, and especially often craniopharyngioma, sarcoidosis. Metastasizes in the pituitary gland more often cancer of the dairy and thyroid glands, bronchi. A number of hemoblastoses are also known - leukemia, erythromyelosis, lymphogranulomatosis, in which infiltration by pathological elements of the blood of the hypothalamus or pituitary gland caused diabetes insipidus. Non-diabetes mellitus accompanies generalized xanthomatosis (Hend-Schüller-Christen disease) and may be one of the symptoms of endocrine diseases or congenital syndromes with impaired hypothalamic-pituitary functions: Simmonds, Shien and Lawrence-Moon-Biddle syndromes, pituitary nanism, acromegalia, gigantism, adiposogenital dystrophy.

However, in a significant number of patients (60-70%), the etiology of the disease remains unknown - idiopathic diabetes insipidus. Among idiopathic forms it is necessary to distinguish genetic, hereditary, observed sometimes in three, five and even seven subsequent generations. The type of inheritance is both autosomal dominant and recessive.

The combination of sugar and diabetes insipidus is also more common among family forms. Currently, it is suggested that in some patients with idiopathic diabetes insipidus, the autoimmune nature of the disease with damage to the hypothalamic nuclei is possible, similar to the destruction of other endocrine organs in autoimmune syndromes. Nephrogenic diabetes insipidus is more often observed in children and is caused either by anatomic inferiority of renal nephron (congenital malformations, cystic degenerative and infectious-dystrophic processes): amyloidosis, sarcoidosis, methoxyflurane poisoning, lithium, or functional enzyme defect: cAMP production in renal tubule cells or a decrease in sensitivity to its effects.

Hypothalamic-pituitary forms of diabetes insipidus with a deficiency of vasopressin secretion can be associated with the defeat of any part of the hypothalamic-neurohypophysis system. The pairing of the neurosecretory nuclei of the hypothalamus and the fact that not less than 80% of the cells secreting vasopressin should be affected for clinical manifestation, provide great opportunities for internal compensation. The greatest probability of occurrence of diabetes insipidus is in cases of lesions in the hypophysis funnel, where neurosecretory pathways connecting from the hypothalamic nuclei combine.

Insufficiency of vasopressin reduces the reabsorption of fluid in the distal part of the renal nephron and promotes the release of a large amount of hypoosmolar non-concentrated urine. Primary polyuria leads to a general dehydration with loss of intracellular and intravascular fluid with hyperosmolarity (above 290 mosm / kg) of plasma and a thirst indicating a violation of aqueous homeostasis. It has now been established that vasopressin causes not only antidiuresis, but also sodium naresis. With hormone deficiency, especially during the period of dehydration, when sodium is also stimulated by the retarding effect of aldosterone, sodium is retained in the body, causing hypernatremia and hypertonic (hyperosmolar) dehydration.

Enhanced enzymatic inactivation of vasopressin in the liver, kidneys, placenta (during pregnancy) causes relative insufficiency of the hormone. Non-diabetes mellitus during pregnancy (transient or further stable) can also be associated with a decrease in the osmolar thirst threshold, which increases water intake, "dissolves" plasma and reduces the level of vasopressin. Pregnancy often worsens the course of pre-existing diabetes insipidus and increases the need for medications. Congenital or acquired refractory kidneys to endogenous and exogenous vasopressin also creates a relative deficiency of the hormone in the body.

[13], [14], [15], [16], [17], [18], [19]

Pathogenesis

True diabetes insipidus develops as a result of damage to the hypothalamus and / or neurohypophysis, with the destruction of any part of the neurosecretory system formed by the supraoptic and paraventricular nuclei of the hypothalamus, the fibrous tract of the leg and the posterior lobe of the pituitary, accompanied by atrophy of the rest of its parts, as well as damage to the funnel. In the nuclei of the hypothalamus, mainly in the supra-optical, a decrease in the number of large-cell neurons and heavy glia is observed. Primary tumors of the neurosecretory system account for up to 29% of cases of diabetes insipidus, syphilis - up to 6%, and trauma to the skull and metastasis to various parts of the neurosecretory system - up to 2-4%. Tumors of the anterior lobe of the pituitary gland, especially large ones, contribute to the development of edema in the funnel and the posterior lobe of the pituitary gland, which in turn lead to the development of diabetes insipidus. The cause of this disease after surgery in the suprasellar region is damage to the pituitary foot and its vessels, followed by atrophy and the disappearance of large nerve cells in the supraoptic and / or paraventricular nuclei and atrophy of the posterior lobe. In a number of cases, these phenomena are reversible. Postnatal damage to the adenohypophysis (Shien syndrome) due to thrombosis and hemorrhage in the pituitary foot and the interruption of the neurosecretory path due to this also lead to diabetes insipidus.

Among the hereditary variants of diabetes insipidus there are cases with reduction of nerve cells in supraoptic and less often in paraventricular nuclei. Similar changes are observed in family cases of the disease. Defects of vasopressin synthesis in the paraventricular nucleus are rarely detected.

Acquired nephrogenic diabetes insipidus can be combined with nephrosclerosis, polycystic kidney disease and congenital hydronephrosis. In this case, in the hypothalamus there is hypertrophy of the nuclei and all parts of the pituitary gland, and in the adrenal cortex - hyperplasia of the glomerular zone. With nephrogenic vasopressin-resistant diabetes insipidus, the kidneys are rarely changed. Sometimes there is an enlargement of renal pelvis or dilatation of collecting tubules. Supraoptic nuclei are either unchanged or somewhat hypertrophied. A rare complication of the disease is a massive intracranial calcification of the white matter of the cerebral cortex from the frontal to the occipital lobes.

According to recent years, idiopathic diabetes insipidus is often associated with autoimmune diseases and organ-specific antibodies to vasopressin secreting and, more rarely, oxytocin secreting cells. In the corresponding structures of the neurosecretory system, lymphoid infiltration with the formation of lymphoid follicles and sometimes a significant replacement of the parenchyma of these structures with lymphoid tissue is detected.

[20], [21], [22], [23], [24], [25]

Symptoms of the diabetes insipidus

The onset of the disease is usually acute, sudden, less common symptoms of diabetes insipidus appear gradually and increase in intensity. The course of diabetes insipidus is chronic.

The severity of the disease, i.e. The severity of polyuria and polydipsia, depends on the degree of neurosecretory insufficiency. With an incomplete vasopressin deficiency, clinical symptoms may not be as clear-cut, and these forms require careful diagnosis. The amount of liquid drunk varies from 3 to 15 liters, but sometimes the painful thirst, which does not let the sick go day or night, requires 20-40 or more liters of water to saturate. In children, rapid nighttime urination (nocturia) may be the initial sign of the disease. The excreted urine is discolored, does not contain any pathological elements, the relative density of all portions is very low - 1000-1005.

Polyuria and polydipsia are accompanied by physical and mental asthenia. Appetite is usually reduced, and patients lose in the mass of the body, sometimes with primary-hypothalamic disorders, on the contrary, obesity develops .

Lack of vasopressin and polyuria affect gastric secretion, bile formation and gastrointestinal motility and cause the appearance of constipation, chronic and hypocidal gastritis, colitis. In connection with constant overload, the stomach is often stretched and dropped. There is dryness of the skin and mucous membranes, a decrease in saliva and sweating. In women, menstrual and reproductive disorders are possible, in men - a decrease in libido and potency. Children often lag behind in growth, physical and sexual maturation.

Cardiovascular system, lungs, the liver usually do not suffer. In severe forms of true diabetes insipidus (hereditary, postinfection, idiopathic) in polyuria, reaching 40-50 or more liters, the kidneys become insensitive to the vasopressin introduced from the outside as a result of overexertion and completely lose the ability to concentrate urine. Thus, the nephrogenic is attached to the primary hypothalamic-insipid diabetes.

Characteristic mental and emotional disorders - headaches, insomnia, emotional imbalance up to psychoses, decreased mental activity. Children - irritability, tearfulness.

In cases when the fluid lost in urine is not replenished (depression of sensitivity of the center of "thirst", lack of water, dehydration test with "dryness"), symptoms of dehydration appear: severe general weakness, headaches, nausea, vomiting (aggravating dehydration), fever, blood thickening (with increasing sodium, erythrocytes, hemoglobin, residual nitrogen), convulsions, psychomotor agitation, tachycardia, hypotension, collapse. These symptoms of hyperosmolar dehydration are especially characteristic of congenital nephrogenic diabetes insipidus in children. Along with this, with nephrogenic diabetes insipidus, sensitivity to vasopressin may be partially retained.

During dehydration, despite the decrease in the volume of circulating blood and the decrease in glomerular filtration, the polyuria is preserved, the urine concentration and its osmolarity almost do not increase (relative density 1000-1010).

Non-diabetes mellitus after surgery on the pituitary or hypothalamus may be transient or permanent. After accidental injury, the course of the disease is unpredictable, as spontaneous recoveries are observed after a few (up to 10) years after the injury.

Non-diabetes in some patients is combined with sugar. This is explained by the neighboring localization of the hypothalamic centers regulating the water and carbohydrate volumes and the structural and functional proximity of the neurons of the hypothalamic nuclei producing vasopressin and B cells of the pancreas.

[26], [27], [28], [29], [30], [31]

Diagnostics of the diabetes insipidus

In typical cases, the diagnosis is not difficult and is based on the detection of polyuria, polydipsia, plasma hyperosmolarity (greater than 290 mosm / kg), hypernatremia (greater than 155 meq / L), urine hypoosmolarity (100-200 mosm / kg) with low relative density. Simultaneous determination of osmolality of plasma and urine provides reliable information about the disturbance of water homeostasis. To clarify the nature of the disease, carefully analyze the history and results of radiologic, ophthalmological and neurological examinations. If necessary, resort to computed tomography. Of decisive importance in diagnosis could be the determination of basal and stimulated plasma levels of vasopressin, but this study is inaccessible to clinical practice.

[32], [33], [34],

Differential diagnosis

Non-diabetes mellitus is differentiated with a number of diseases that occur with polyuria and polydipsia: diabetes mellitus, psychogenic polydipsia, compensatory polyuria in the azotemic stage of chronic glomerulonephritis and nephrosclerosis.

Nephrogenic vasopressin-resistant diabetes insipidus (congenital and acquired) is differentiated from polyuria arising from primary aldosteronism, hyperparathyroidism with nephrocalcinosis, and syndrome of impaired adsorption in the intestine.

Psychogenic polydipsia - idiopathic or in connection with mental illness - is characterized by a primary thirst. It is caused by functional or organic disorders in the center of thirst, resulting in uncontrolled intake of large amounts of fluid. Increasing the volume of the circulating fluid reduces its osmotic pressure and, through the system of osmoregulatory receptors, reduces the level of vasopressin. So (secondarily) there is a polyuria with a low relative density of urine. Osmolarity of the plasma and the level of sodium in it are normal or somewhat reduced. Restriction of fluid intake and dehydration, stimulating endogenous vasopressin in patients with psychogenic polydipsia, in contrast to patients with diabetes insipidus, do not disrupt the general condition, the amount of urine released is correspondingly reduced, and its osmolarity and relative density are normalized. However, with prolonged polyuria, the kidneys gradually lose the ability to respond to vasopressin with the maximum increase in osmolarity of urine (up to 900-1200 mosm / kg), and even with primary polydipsia, normalization of relative density may not occur. In patients with diabetes insipidus, with a decrease in the amount of fluid taken, the general condition worsens, thirst becomes painful, dehydration develops, and the amount of urine released, its osmolarity and relative density do not change significantly. In this regard, a dehydrated differential diagnostic test with dryness should be performed in a hospital and its duration should not exceed 6-8 hours. The maximum duration of the sample with good tolerability is 14 hours. During the test, the urine is collected every hour. Its relative density and volume is measured in each hourly portion, and body weight - after each liter of the extracted urine. The absence of significant dynamics of relative density in the next two portions with a loss of 2% of body weight indicates the lack of stimulation of endogenous vasopressin.

For the purpose of differential diagnosis with psychogenic polydipsia, a sample with an intravenous injection of 2.5% sodium chloride solution is sometimes used (50 ml is injected for 45 minutes). In patients with psychogenic polydipsia, an increase in the osmotic concentration in the plasma rapidly stimulates the release of endogenous vasopressin, the amount of urine released decreases, and its relative density increases. In diabetes insipidus, the volume and concentration of urine does not change significantly. It should be noted that children are very hard to tolerate the test with salt load.

The introduction of vasopressin drugs with true diabetes insipidus reduces polyuria and, accordingly, polydipsia; while with psychogenic polydipsia, in connection with the introduction of vasopressin, headaches and symptoms of water intoxication may appear. With nephrogenic diabetes insipidus, the administration of vasopressin drugs is ineffective. Currently, for diagnostic purposes, the suppressive effect of the synthetic analogue of vasopressin on factor VIII of blood coagulation is used. In patients with latent forms of nephrogenic diabetes insipidus and in families at risk of disease, there is no suppression effect.

In case of diabetes, polyuria is not as great as in non-sugar, and urine is hypertensive. In the blood - hyperglycemia. When combined sugar and diabetes insipidus glucosuria increases the concentration of urine, but even with a high content of sugar in it, its relative density is reduced (1012-1020).

With compensatory azotemic polyuria diuresis does not exceed 3-4 liters. Hypoisostenuria is observed with fluctuations in the relative density of 1005-1012. In the blood, the level of creatinine, urea and residual nitrogen is increased, in the urine - red blood cells, protein, cylinders. A number of diseases with dystrophic changes in the kidney and vasopressin-resistant polyuria and polydipsia (primary aldosteronism, hyperparathyroidism, disrupted adsorption syndrome in the intestine, Fanconi nephronophytosis, tubulopathy) should be differentiated with nephrogenic diabetes insipidus.

At primary aldosteronism, hypokalemia is noted, which causes dystrophy of the epithelium of the renal tubules, polyuria (2-4 L), hypoisostenuria.

Hyperparathyroidism with hypercalcemia and nephrocalcinosis, which inhibits vasopressin binding by the tubular receptors, causes mild polyuria and hypoisostenuria.

With the syndrome of impaired adsorption in the intestine ("malabsorption syndrome") - depleting diarrhea, impaired absorption in the intestine of electrolytes, protein, vitamins, hypoisostenuria, moderate polyuria.

Nephronophthisis Fanconi is a congenital disease in children - in the early stages it is characterized only by polyuria and polydipsia, further reduction of calcium level and increase in phosphorus in the blood, anemia, osteopathy, proteinuria and kidney failure.

Treatment of the diabetes insipidus

Treatment of diabetes insipidus is primarily etiologic. Symptomatic forms require the elimination of the underlying disease.

With tumors of the pituitary or hypothalamus - surgical intervention or radiation therapy, the introduction of radioactive yttrium, cryodestruction. In the inflammatory nature of the disease - antibiotics, specific anti-inflammatory drugs, dehydration. With hemoblastosis - therapy with cytostatic agents.

Regardless of the nature of the primary process, all forms of the disease with insufficient vasopressin production require substitution therapy. Until recently, the most common drug was adiurecrin powder for intranasal use, containing the vasopressor activity of the extract of the posterior lobe of the pituitary gland of cattle and pigs. Inhalation of 0,03-0,05 g of adiurecrin after 15-20 minutes gives an antidiuretic effect that lasts 6-8 hours. With good sensitivity and tolerance of the drug, 2-3-fold inhalation during the day reduces the amount of urine to 1.5-3 l and eliminates thirst. Children receive the drug as an ointment, but its effectiveness is low. In inflammatory processes in the nasal mucosa, absorption of adiurecrin is impaired, and the effectiveness of the drug is sharply reduced.

Subcutaneous administration of pituitrin (water-soluble extract of the posterior lobe of the pituitary gland of slaughter cattle containing vasopressin and oxytocin) is more difficult to tolerate by patients, requires systematic injections (2-3 times per day for 1 ml - 5 units), more often causes allergic reactions and symptoms of overdose. With excessive intake of both adiurecrin and pituitrin, symptoms of water intoxication appear: headaches, abdominal pain, diarrhea, fluid retention.

In recent years, instead of adiurecrin, a synthetic analogue of vasopressin, adiuretin, is used more often, a drug with a pronounced antidiuretic effect and completely devoid of vasopressor properties. According to clinical tolerability and efficacy, it significantly exceeds adiurecrin. It is administered intranasally - 1-4 drops in each nostril 2-3 times a day. It is recommended to use minimally effective doses, since overdose causes fluid retention and hyponatremia, i.e. Imitates the syndrome of inappropriate production of vasopressin.

Abroad, the intranasal synthetic analogue of vasopressin (1-desamino-8D-arginine vasopressin - DDAVP) is successfully used. However, there are isolated reports about the possibility of allergic reactions when taking DDAPV. It is reported about the effective administration of this drug or hydrochlorothiazide in combination with indomethacin, which blocks the synthesis of prostaglandins in children with nephrogenic diabetes insipidus. Synthetic analogues of vasopressin can improve the condition of patients with nephrogenic diabetes, in which sensitivity to vasopressin is partially preserved.

Paradoxical symptomatic effect in diabetes insipidus, hypothalamic and nephrogenic, give diuretic preparations of thiazide group (for example, hypothiazide - 100 mg per day), reducing glomerular filtration and sodium excretion with a decrease in the amount of urine output by 50-60%. In this case, the excretion of potassium is increased, in connection with which it is necessary to constantly monitor its level in the blood. The effect of thiazide drugs is not observed in all patients and is weakened over time.

Oral hypoglycemic drug chlorpropamide is also effective in a number of patients with diabetes insipidus, especially when combined with diabetes mellitus, in a daily dose of 250 mg 2-3 times a day. The mechanism of its antidiuretic action is not fully elucidated. It is assumed that chlorpropamide is effective only if the body has at least a minimum amount of its own vasopressin, the effect of which it potentiates. Stimulation of the synthesis of endogenous vasopressin and an increase in the sensitivity of the renal tubules to it are not ruled out. The therapeutic effect is manifested after the 3rd-4th day of treatment. To avoid hypoglycemia and hyponatremia during the application of chlorpropamide, it is necessary to monitor the level of glucose and sodium in the blood.

Forecast

The ability to work for patients with diabetes insipidus depends on the degree of compensation of disturbed water metabolism, and in symptomatic forms - on the nature and course of the underlying disease. The use of adiuretin allows many patients to fully restore water homeostasis and work capacity.

At present, it is not known how to prevent "idiopathic" diabetes insipidus. Prevention of symptomatic forms of it is based on timely diagnosis and treatment of acute and chronic infections, craniocerebral trauma, including birth and intrauterine, brain and pituitary tumors (see etiology).

[35], [36], [37],