Non-diabetes mellitus

Diabetes insipidus is a disease characterized by diabetic exhaustion, increased plasma osmolarity, which stimulates the thirst mechanism, and compensatory consumption of large amounts of fluid.

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Epidemiology

The incidence of diabetes insipidus is not specified. It is estimated at 0.5-0.7% of the total number of patients with endocrine pathology. The disease occurs equally in both sexes at any age, but more often at 20-40 years. Congenital forms can be present in children from the first months of life, but are sometimes detected much later.

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Causes non-sugar diabetes

Diabetes insipidus is caused by a deficiency of vasopressin, which controls the reabsorption of water in the distal tubules of the renal nephron, where, under physiological conditions, negative clearance of “free” water is ensured on the scale necessary for homeostasis, and urine concentration is completed.

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

The central forms of diabetes insipidus may be caused by inflammatory, degenerative, traumatic, tumor, etc. lesions of various parts of the hypothalamic-neurohypophyseal system (anterior nuclei of the hypothalamus, supraopticohypophyseal tract, posterior pituitary gland). 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 types of typhus, septic conditions, tuberculosis, syphilis, malaria, brucellosis, rheumatism. Influenza with its neurotropic effect is more common than other infections. As the overall incidence of tuberculosis, syphilis, and other chronic infections decreases, their causal role in the development of diabetes insipidus has significantly decreased. The disease can occur after a traumatic brain injury (accidental or surgical), mental trauma, electric shock, hypothermia, during pregnancy, shortly after childbirth, or abortion.

Diabetes insipidus in children can be caused by birth trauma. Symptomatic diabetes insipidus is caused by primary and metastatic tumors of the hypothalamus and pituitary gland, adenoma, teratoma, glioma, and especially often craniopharyngioma, sarcoidosis. Breast and thyroid cancer, as well as bronchial cancer, most often metastasize to the pituitary gland. A number of hemoblastoses are also known - leukemia, erythromyelosis, lymphogranulomatosis, in which infiltration of the hypothalamus or pituitary gland with pathological blood elements causes diabetes insipidus. Diabetes insipidus accompanies generalized xanthomatosis (Hand-Schüller-Christian disease) and can be one of the symptoms of endocrine diseases or congenital syndromes with impaired hypothalamic-pituitary functions: Simmonds, Sheehan and Lawrence-Moon-Biedl syndromes, pituitary dwarfism, acromegaly, gigantism, adiposogenital dystrophy.

At the same time, in a significant number of patients (60-70%) the etiology of the disease remains unknown - idiopathic diabetes insipidus. Among the idiopathic forms, genetic, hereditary ones should be distinguished, sometimes observed in three, five and even seven subsequent generations. The type of inheritance is both autosomal dominant and recessive.

The combination of diabetes mellitus and diabetes insipidus is also more common among familial forms. It is currently assumed that some patients with idiopathic diabetes insipidus may have an autoimmune nature of the disease with damage to the hypothalamic nuclei similar to the destruction of other endocrine organs in autoimmune syndromes. Nephrogenic diabetes insipidus is more often observed in children and is caused by either anatomical inferiority of the renal nephron (congenital malformations, cystic-degenerative and infectious-dystrophic processes): amyloidosis, sarcoidosis, poisoning with methoxyflurane, lithium, or a functional enzymatic defect: impaired cAMP production in renal tubule cells or decreased sensitivity to its effects.

Hypothalamic-pituitary forms of diabetes insipidus with insufficient secretion of vasopressin may be associated with damage to any part of the hypothalamic-neurohypophyseal system. The pairing of the neurosecretory nuclei of the hypothalamus and the fact that at least 80% of the cells secreting vasopressin must be damaged for clinical manifestation provide great opportunities for internal compensation. The greatest probability of diabetes insipidus is with damage to the area of the pituitary funnel, where the neurosecretory pathways coming from the hypothalamic nuclei connect.

Vasopressin deficiency reduces fluid reabsorption in the distal part of the renal nephron and promotes the excretion of large amounts of hypoosmolar non-concentrated urine. Primary polyuria results in general dehydration with loss of intracellular and intravascular fluid with hyperosmolarity (above 290 mosm/kg) of plasma and thirst, indicating a disturbance of water homeostasis. It has now been established that vasopressin causes not only antidiuresis, but also natriuresis. In case of hormone deficiency, especially during periods of dehydration, when the sodium-retaining effect of aldosterone is also stimulated, sodium is retained in the body, causing hypernatremia and hypertonic (hyperosmolar) dehydration.

Increased enzymatic inactivation of vasopressin in the liver, kidneys, placenta (during pregnancy) causes relative deficiency of the hormone. Diabetes insipidus during pregnancy (transient or subsequently stable) may also be associated with a decrease in the osmolar threshold of thirst, which increases water consumption, "dilutes" the plasma and reduces the level of vasopressin. Pregnancy often worsens the course of previously existing diabetes insipidus and increases the need for medications. Congenital or acquired renal refractoriness to endogenous and exogenous vasopressin also creates a relative deficiency of the hormone in the body.

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Pathogenesis

True diabetes insipidus develops as a result of damage to the hypothalamus and/or neurohypophysis, with destruction of any part of the neurosecretory system formed by the supraoptic and paraventricular nuclei of the hypothalamus, the fibrous tract of the stalk, and the posterior lobe of the pituitary gland accompanied by atrophy of its remaining parts and damage to the infundibulum. In the nuclei of the hypothalamus, primarily in the supraoptic, there is a decrease in the number of large-cell neurons and severe gliosis. Primary tumors of the neurosecretory system cause up to 29% of cases of diabetes insipidus, syphilis - up to 6%, and cranial trauma and metastases to various links of the neurosecretory system - up to 2-4%. Tumors of the anterior pituitary gland, especially large ones, contribute to the development of edema in the infundibulum and 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 stalk and its vessels with subsequent atrophy and disappearance of large nerve cells in the supraoptic and/or paraventricular nuclei and atrophy of the posterior lobe. These phenomena are reversible in some cases. Postnatal damage to the adenohypophysis (Sheehan's syndrome) due to thrombosis and hemorrhage in the pituitary stalk and the resulting interruption of the neurosecretory pathway also leads to diabetes insipidus.

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

Acquired nephrogenic diabetes insipidus may be combined with nephrosclerosis, polycystic kidney disease, and congenital hydronephrosis. In this case, hypertrophy of the nuclei and all parts of the pituitary gland is observed in the hypothalamus, and hyperplasia of the glomerular zone is observed in the adrenal cortex. In nephrogenic vasopressin-resistant diabetes insipidus, the kidneys are rarely changed. Sometimes, dilation of the renal pelvis or dilation of the collecting ducts is observed. The supraoptic nuclei are either unchanged or slightly hypertrophied. A rare complication of the disease is massive intracranial calcification of the white matter of the cerebral cortex from the frontal to the occipital lobes.

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

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Symptoms non-sugar diabetes

The onset of the disease is usually acute, sudden, less often the 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. In case of partial vasopressin deficiency, the clinical symptoms may not be so distinct, and it is these forms that require careful diagnostics. The amount of liquid drunk varies from 3 to 15 liters, but sometimes the excruciating thirst that does not leave patients either day or night requires 20-40 or more liters of water for saturation. In children, frequent night 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 weight; sometimes, with primary hypothalamic disorders, on the contrary, obesity develops.

Vasopressin deficiency and polyuria affect gastric secretion, bile formation and gastrointestinal motility and cause constipation, chronic and hypoacid gastritis, colitis. Due to constant overload, the stomach often stretches and drops. Dry skin and mucous membranes, decreased salivation and sweating are noted. Women may experience menstrual and reproductive dysfunction, while men may experience decreased libido and potency. Children often lag behind in growth, physical and sexual maturation.

The cardiovascular system, lungs, and liver are usually not affected. In severe forms of true diabetes insipidus (hereditary, postinfectious, idiopathic) with polyuria reaching 40-50 liters or more, the kidneys, as a result of overstrain, become insensitive to vasopressin introduced from outside and completely lose the ability to concentrate urine. Thus, nephrogenic diabetes insipidus is added to primary hypothalamic diabetes insipidus.

Mental and emotional disorders are typical - headaches, insomnia, emotional instability up to psychosis, decreased mental activity. In children - irritability, tearfulness.

In cases where the fluid lost with urine is not replenished (decreased sensitivity of the "thirst" center, lack of water, dehydration test with "xerophagy"), symptoms of dehydration occur: severe general weakness, headaches, nausea, vomiting (aggravating dehydration), fever, thickening of the blood (with an increase in the level of sodium, erythrocytes, hemoglobin, residual nitrogen), convulsions, psychomotor agitation, tachycardia, hypotension, collapse. The above 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 preserved.

During dehydration, despite the decrease in circulating blood volume and the decrease in glomerular filtration, polyuria persists, the concentration of urine and its osmolarity hardly increase (relative density 1000-1010).

Diabetes insipidus after surgery on the pituitary gland or hypothalamus may be transient or permanent. After an accidental injury, the course of the disease is unpredictable, as spontaneous recoveries are observed even several (up to 10) years after the injury.

In some patients, diabetes insipidus is combined with diabetes mellitus. This is explained by the adjacent localization of the hypothalamic centers that regulate water and carbohydrate volumes, and the structural and functional proximity of the neurons of the hypothalamic nuclei that produce vasopressin and B-cells of the pancreas.

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Diagnostics non-sugar diabetes

In typical cases, the diagnosis is not difficult and is based on the detection of polyuria, polydipsia, plasma hyperosmolarity (more than 290 mOsm/kg), hypernatremia (more than 155 mEq/l), urine hypoosmolarity (100-200 mOsm/kg) with low relative density. Simultaneous determination of plasma and urine osmolarity provides reliable information on the disturbance of water homeostasis. To determine the nature of the disease, the anamnesis and the results of radiological, ophthalmological and neurological examinations are carefully analyzed. If necessary, computed tomography is used. Determination of basal and stimulated plasma vasopressin levels could be of decisive importance in diagnostics, but this study is not widely available in clinical practice.

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Differential diagnosis

Diabetes insipidus is differentiated from 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 that occurs with primary aldosteronism, hyperparathyroidism with nephrocalcinosis, and intestinal malabsorption syndrome.

Psychogenic polydipsia - idiopathic or due to mental illness - is characterized by primary thirst. It is caused by functional or organic disorders in the thirst center, leading to uncontrolled intake of large amounts of fluid. An increase in the volume of circulating fluid reduces its osmotic pressure and, through the system of osmoregulatory receptors, reduces the level of vasopressin. Thus (secondarily) polyuria with a low relative density of urine occurs. Plasma osmolarity and sodium level in it are normal or slightly reduced. Limitation of fluid intake and dehydration, stimulating endogenous vasopressin in patients with psychogenic polydipsia, unlike patients with diabetes insipidus, do not disturb the general condition, the amount of excreted urine decreases accordingly, and its osmolarity and relative density are normalized. However, with prolonged polyuria, the kidneys gradually lose the ability to respond to vasopressin by maximally increasing urine osmolarity (up to 900-1200 mosm/kg), and even with primary polydipsia, normalization of the relative density may not occur. In patients with diabetes insipidus, with a decrease in the amount of fluid taken in, the general condition worsens, thirst becomes excruciating, dehydration develops, and the amount of excreted urine, its osmolarity and relative density do not change significantly. In this regard, the dehydration differential diagnostic test with xerophagy should be carried out in a hospital setting, and its duration should not exceed 6-8 hours. The maximum duration of the test with good tolerance is 14 hours. During the test, urine is collected every hour. Its relative density and volume are measured in each hourly portion, and body weight - after each liter of excreted urine. The absence of significant dynamics of the relative density in the two subsequent portions with a loss of 2% of body weight indicates the absence of stimulation of endogenous vasopressin.

For the purpose of differential diagnosis with psychogenic polydipsia, a test with intravenous administration of 2.5% sodium chloride solution is sometimes used (50 ml is administered over 45 minutes). In patients with psychogenic polydipsia, an increase in the osmotic concentration in the plasma quickly stimulates the release of endogenous vasopressin, the amount of excreted urine decreases, and its relative density increases. In diabetes insipidus, the volume and concentration of urine do not change significantly. It should be noted that children tolerate the salt load test very poorly.

Administration of vasopressin preparations in true diabetes insipidus reduces polyuria and, accordingly, polydipsia; however, in psychogenic polydipsia, headaches and symptoms of water intoxication may occur due to administration of vasopressin. Administration of vasopressin preparations is ineffective in nephrogenic diabetes insipidus. Currently, the suppressive effect of a synthetic analogue of vasopressin on blood coagulation factor VIII is used for diagnostic purposes. In patients with latent forms of nephrogenic diabetes insipidus and in families at risk of the disease, the suppressive effect is absent.

In diabetes mellitus, polyuria is not as great as in diabetes insipidus, and the urine is hypertonic. There is hyperglycemia in the blood. In a combination of diabetes mellitus and diabetes insipidus, glucosuria increases the concentration of urine, but even with a high sugar content, its relative density is reduced (1012-1020).

In compensatory azotemic polyuria, diuresis does not exceed 3-4 liters. Hypoisosthenuria with fluctuations in relative density of 1005-1012 is observed. The level of creatinine, urea and residual nitrogen in the blood is increased, in the urine - erythrocytes, protein, cylinders. A number of diseases with dystrophic changes in the kidneys and vasopressin-resistant polyuria and polydipsia (primary aldosteronism, hyperparathyroidism, intestinal malabsorption syndrome, Fanconi nephronophthisis, tubulopathy) should be differentiated from nephrogenic diabetes insipidus.

In primary aldosteronism, hypokalemia is observed, causing dystrophy of the epithelium of the renal tubules, polyuria (2-4 l), and hypoisosthenuria.

Hyperparathyroidism with hypercalcemia and nephrocalcinosis, which inhibits the binding of vasopressin to tubular receptors, causes moderate polyuria and hypoisosthenuria.

In case of impaired intestinal absorption syndrome (“malabsorption syndrome”) - debilitating diarrhea, impaired intestinal absorption of electrolytes, protein, vitamins, hypoisosthenuria, moderate polyuria.

Fanconi nephronophthisis is a congenital disease in children - in the early stages it is characterized only by polyuria and polydipsia, later on it is accompanied by a decrease in calcium levels and an increase in phosphorus in the blood, anemia, osteopathy, proteinuria and renal failure.

Treatment non-sugar diabetes

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

In case of pituitary or hypothalamic tumors - surgical intervention or radiation therapy, introduction of radioactive yttrium, cryodestruction. In case of inflammatory nature of the disease - antibiotics, specific anti-inflammatory agents, dehydration. In case of hemoblastoses - therapy with cytostatic agents.

Regardless of the nature of the primary process, all forms of the disease with insufficient vasopressin production require replacement therapy. Until recently, the most common drug was adiurecrin powder for intranasal use, containing the vasopressor activity of the extract of the posterior pituitary gland of cattle and pigs. Inhalation of 0.03-0.05 g of adiurecrin after 15-20 minutes produces 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 liters and eliminates thirst. Children are given the drug in the form of an ointment, but its effectiveness is low. In inflammatory processes in the nasal mucosa, the absorption of adiurecrin is impaired, and the effectiveness of the drug is sharply reduced.

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

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

Abroad, an intranasal synthetic analogue of vasopressin (1-deamino-8D-arginine vasopressin - DDAVP) is successfully used. However, there are isolated reports of the possibility of allergic reactions when taking DDAVP. There are reports of 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 who have partially retained sensitivity to vasopressin.

A paradoxical symptomatic effect in diabetes insipidus, hypothalamic and nephrogenic, is provided by diuretics of the thiazide group (for example, hypothiazide - 100 mg per day), reducing glomerular filtration and sodium excretion with a decrease in the amount of excreted urine by 50-60%. At the same time, potassium excretion increases, 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 weakens over time.

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

Forecast

The ability to work of patients with diabetes insipidus depends on the degree of compensation for impaired 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 unknown how to prevent "idiopathic" diabetes insipidus. Prevention of its symptomatic forms is based on timely diagnosis and treatment of acute and chronic infections, craniocerebral injuries, including birth and intrauterine, brain and pituitary tumors (see etiology).

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