Diabetes insipidus pathology
Genetic diabetes mellitus is often associated with diabetes mellitus, atrophy of the eyes, deafness, and diabetes mellitus with impaired circulation ADH
Diabetes mellitus (MS) is a medical condition caused by the inability to reabsorb water in the renal tubules, resulting from a relative or absolute lack of ADH leading to excessive urination, excessive drinking, low-density urine and drinking. In many cases, the disease may occur due to poor ADH release (diabetes mellitus or neurology) or the kidneys respond poorly to ADH (diabetes mellitus). There are about 50% of MSM cases with an unknown cause.
ADH (antidiuretic hormone) is secreted from the hypothalamus, from where it reaches the posterior pituitary. ADH acts on water regulation by regulating renal water reabsorption.
Human ADH is also known as arginine-vasopressin (AVP) is a polypeptide with eight amino acids (octapeptides). In pigs, arginine was replaced with lysine (LVP). Notably, in people, LVP can also stimulate ACTH secretion.
With a plasma osmolality of 280mOsm / kg, the measured ADH in the blood is <2 pmol/l (= pg / ml), the ADH will increase to 10-12pmol / l when the blood permeability reaches 310mOsm / Kg. The half-life of ADH is very short: 10-20 minutes. ADH is broken down rapidly by enzymes in the target organ mainly in the kidney (2/3), the rest is broken down in the liver (1/3).
Plasma permeability = (blood sodium + blood potassium) x 2 + blood urea + blood glucose. All in mM / l. Normal value: 290-300mOsm / kg
The main effect of ADH occurs in the kidneys, ADH saves free water. The kidneys filter 120 ml of water/minute (or 172 litters / 24h). More than 85% of water is required to be reabsorbed in the tubule close to Na +, thus 23.5 liters is reabsorbed due to the role of ADH.
Lack of absolute ADH will inevitably cause water loss if not drinking enough. However, the reality shows that the urinary retention due to lack of ADH does not exceed 8-12 litres (1/2 of the theoretical amount of 23.5 liter ADH dependent).
Mechanism of action
ADH works through two types of receptors V1 and V2:
V1 receptors constrict the smooth muscle of blood vessels, stimulate prostaglandin synthesis and glycogen breakdown in the liver. Effects on this receptor increase phosphatidylinositol decomposition causing calcium mobilization.
V2 receptors are responsible for the vasopressin effect on the kidneys. ADH increases the water permeability of the epidermis of the manifold. Lack of ADH is reduced water reabsorption resulting in excessive urination. With ADH, in contrast, the permeability of the epidermis increases, the water is reabsorbed. This effect occurs because ADH binds to the V2 receptor.
Cardiovascular ADH acts on V1 receptors on peripheral arterioles to increase blood pressure. However, ADH itself slows the heart rate, inhibits sympathetic nerves, and reduces the effect of hypertension. Anyway, the blood pressure-raising effect may be prominent when the blood volume is reduced then the plasma ADH is very high.
Regarding the role of V1 receptors, V2 has many disagreements. As for the V2 receptor, everyone agrees when stimulation increases water reabsorption.
With V1 receptors, it is suggested that V1 reduces the anti-diuretic response of AVP in the kidney.
Regulates ADH secretion
Osmotic pressure and plasma volume are the two most important factors.
Factors that stimulate ADH secretion:
Nervous factors: emotion, pain, movement.
Pharmaceutical substances: acetylcholine, morphine, nicotine.
Osmotic factors: Hypertonic solution infusion, increased plasma osmolality, decreased plasma volume.
Factors that inhibit ADH secretion:
Medicinal substances: Adrenaline, Alcohol.
Osmotic factor: Infusion of the hypotonic solution, reducing plasma osmotic pressure.
Increased plasma volume.
Central diabetes insipidus (nerve insipidus)
Lesions to the hypothalamus that cause pituitary insufficiency may be the cause of diabetes, diabetes. lesions of the hypothalamus, such as craniopharyngiomas or other central nerve damage due to infiltration, are more likely to lead to insipidus.
Diabetes insipidus can also be caused by trauma, or from surgery for hypothalamic and pituitary tumours.
Family-borne diabetes insipidus is a rare, genetic disease that occurs at a young age.
Idiopathic diabetes usually occurs in late childhood, adolescence, and adulthood, and often has a decrease in the number of ADH-containing nerve fibres. Approximately 30-40% of patients with direct antibodies to hypothalamic neurons secret ADH.
Genetic diabetes mellitus is often associated with diabetes mellitus, atrophy of the eyes, deafness, diabetes mellitus with an impaired circulation of ADH enzymes due to increased Vasopressin’s enzyme occurring during pregnancy.
Diabetes pale kidney
The disease occurs because the kidneys do not respond to the physiological effects of ADH, in which case the ADH in the blood is normal or increased.
Chronic kidney diseases, especially those that damage the medulla region, and the collecting tubes can lead to insipidus in the kidneys.
Electrolyte disorders: Hypokalaemia, hypercalcemia reduce the ability to concentrate urine.
There are many drugs that contribute to the development of diabetes insipidus caused by kidneys such as lithium, Demeclocycline, Methoxyflurane, Amphotericin B, Aminoglycosides, Cisplatin, Rifampicin.
During pregnancy, an aminopeptidase from the placenta increases AVP metabolism causing deficiency
AVP leads to excessive urination ..
Drink a lot first (potomania habit)
In fact, not diabetes, patients drink a lot due to psychology. The amount of drinking water can be more than the actual MSM case. The disease is often found on a psychotic site, and it occurs slowly after a trauma. Distinguishing from diabetes mellitus on the method of fasting thirst.
The clinical symptoms of diabetes insipidus can appear suddenly, progress rapidly with 2 symptoms of urination a lot and drinking a lot.
Urinate a lot
As the main symptom of diabetes insipidus, urine output from 5 -10l / day, sometimes up to 15 -
20l / day, sometimes less, but especially thin urine-like water.
Thirst and drinking a lot
Always accompanied by urinary incontinence with 3 characteristics of thirst a lot, constantly, not quitting thirst.
The thirst woke the patient up during the night.
The patient's condition is still good, except for the case of diabetes insipidus with damage that destroys the hypothalamus-pituitary gland.
If the patient is unable to drink (for example, coma due to traumatic brain injury, anaesthetics ...) can lead to death.
In cases of traumatic brain injury or head, surgery can develop this condition, it is necessary to monitor the amount of urine, plasma concentrations and urine in the comatose patient to help prevent severe dehydration. Diabetes insipidus was not diagnosed.
Very rarely, diabetes insipidus with the destruction of the thirst centre rapidly exacerbates the disease and leads to death.
Cases of urethral stenosis accompanied by fluid retention are also rare.
The proportion of fasting early morning urine <1.005.
Urine osmolar pressure 200 mOsm / kg water.
If the disease is still taken fully, often biological tests appear to be normal such as:
Normal blood count, there may be mild anaemia caused by blood thinning.
The electrolyte is completely normal (blood).
Normal urinary electrolyte / 24h.
Confirming diagnosis must be based on dynamic tests, which are both to diagnose the origin of the disorder and to distinguish a diabetes insipidus from a potomania.
In patients with diabetes mellitus, kinetic tests aim to evaluate on the one hand whether water restriction stimulates ADH secretion, and on the other hand, the number of hormones secreted to reduce diabetes mellitus.
Test for quenching thirst:
Need to do it in the hospital because a dangerous accident can happen. The goal is to see if ADH is capable of excretion.
Allow the patient to urinate completely, weigh the patient and lie down.
Angioplasty, HA every 15 minutes, urine every 30 minutes. Continue monitoring for as long as the patient can tolerate, not discomfort.
The alarming symptoms are anxiety, the onset of dehydration such as mucosal dryness, increased thirst, rapid pulse, especially low BP. The test must be stopped when the weight falls to 3% of the body weight.
In ordinary people:
The amount of urine decreased <5ml / min. The proportion of urine (1,020 gradually increased. In patients with diabetes insipidus:
The amount of urine is greater than 5ml / min
Urine osmolality <200 mosm / kg H2O Density 1,001 - 1,005
The methods to stimulate secretion of ADH:
Classic has Carter and Robbins test or improved J. Deccourt test or nicotine test, which is intended to stimulate ADH secretion under the action of a saline pass.
The current tests are rarely used. Or test the hypertonic saline pass and quantify ADH. In diabetes, ADH will not increase (Robertson 1980).
In general, these tests are rarely used.
Special tests for both diagnosis and treatment exploration:
Chlorothiazide is normally a sodium chloride loss diuretic. In patients with diabetes mellitus, oral administration of Chlorothiazide inconsistently reduces urination without negative free water clearance. The mechanism is not well understood. There is a theory that diabetes improves due to the loss of salt in the drug. This test is used less and less.
Specific treatment tests:
Chlorpropamide enhances renal tubular ADH activity.
Clofibrate and Carbamazepine work to stimulate the hypothalamus to increase ADH secretion. Free water discharge is measured for 24 hours or in urine samples taken from 3 periods (8-14 hours, 14 hours - 19 hours, 19 hours - 8 hours). The drug will decrease urine output, and most are increased urine concentration.
If the free water clearance returns to negative, it is allowed to conclude that the drug works well.
These tests are of importance in the future long-term treatment of patients.
Use posterior pituitary extract:
To distinguish diabetes insipidus due to lack of ADH and diabetes insipidus by the kidney. Pitressin 5 / 1000vnd / v (5 milliunits) slow IV infusion for one hour or 5 units of vasopressin tannate oil intramuscularly will decrease MS due to lack of ADH, but not if diabetes insipidus due to kidney resistance to the effects of ADH.
Quantification of ADH by immunofluorescence
Concentrations may be normal, but not increased, in the hydration test, in the salt increase test.
In renal diabetes insipidus, basal ADH levels are elevated.
The treatment is structurally similar to AVP
DRUG: Minirin .
Presentation: The drug is presented in 2 forms: Nasal spray, bottle containing 2.5ml. Inject form, 4μg / ml. Store at +2 to +8 0 C.
This is the drug of choice for the first time in the treatment of diabetes mellitus. Particularly, the injection form is indicated for patients with central diabetes mellitus, but patients cannot use the spray form due to discomfort or insipid after neurosurgery or trauma.
Desmopressin is structurally similar to natural ADH. However, in comparison with natural ADH desmopressin has a stronger and longer-lasting effect against urination (effect on V2 receptors), but other effects on V1 receptors are less than AVP. After injecting 1-4μg TM dose only 15-30 minutes later is effective in reducing urination, the effect lasts 5 to 20 hours depending on the dose. With a higher dose (0.3-0.4μg / kg of body weight), the drug can increase factor VIII and von Willebrand by 3-4 times the baseline concentration. At a dose of 0.4μg / kg of body weight, the drug has a vasodilator effect, the face is red, diastolic blood pressure drops and the heart rate increases transiently. By nasal spray, only 2 times/day is enough.
With nasal spray: Adults 0.1-0.2ml (10-20μg). Children 0.05-0.1ml (5-10μg) 1-2 times a day. Usually, each bottle of Minirin contains 25 sprays, each spray contains 0.1ml ie 10μg desmopressin.
With injection form: can inject IV, corn or subcutaneously 1-2 times / day. Adults: 1-4μg (0.25-1ml). Children over 1 year: 0.4-1μg (0.10-0.25ml). Children aged 1 year and younger: 0.2-0.4μg (0.05-0.10ml).
Hypersensitivity to the ingredients of the drug used. Pregnancy, lactation.
Although the drug has little effect on V1 receptors, does not have much effect on the heart, but when used concurrently with other vasopressors should also be cautious.
The anti-urination effects may change when taking other drugs together:
Clofibrate, indomethacin, carbamazepine, chlorpropamide: increase the anti-urination effect.
Glipalamide: reduced anti-urination effect.
Brand name, presentation, pharmacokinetics:
Diapsid, presented in the form of a nasal spray. 12ml bottle. Store at + 2o to + 15o. A synthetic drug with an AVP-like structure stimulates water reabsorption in the distal tubule.
Treatment of diabetes mellitus due to lack of ADH of any aetiology.
One spray per nostril, 3-6 times/day, must be spaced at least 4 hours between sprays (Each spray releases 0.12ml of solution ie 6v / v lypressine. Each spray can be 100 times). Not valid for coronary insufficiency, drug hypersensitivity, halogen anaesthesia, pregnant women, lactating women.
Brand name, presentation, pharmacokinetics:
Dabinese (Pfizer), Diabetoral (Boehring Mannheim), Chloronase (Hoechst) presented in the form of tablets, content of 250mg / tablet. Drugs belonging to the first generation sulfonylurease group to lower blood glucose, particularly for diabetes mellitus, at a dose of 250-500mg / day the drug increases the permeability of the urine and reduces urination by 25-75% in patients. Severe MSM. however, the time it takes for the drug to work to reduce urination is variable. The drug enhances the activity of ADH in the renal tubules. An important side effect is a hypoglycaemia.
Diabetes Type 2, diabetes mellitus central, can be used in combination with DDAVP, diabetes insipidus.
250-500mg / day. Contraindicated in severe hepatic, renal or hypothyroidism, a history of allergy to sulfamide, pregnant women, lactating women.
Brand name, presentation, pharmacokinetics:
Lipavlon (ICI; Avlon), Atromid (ICI), Clofibral (Negma), Normolipol (Delagrange) ... Presented in tablet form, content of 500mg. The drug is known to be mainly used in the treatment of increased VLDL, LDL cholesterol, and triglycerides. In addition, the drug also works to reduce urination like chlorpropamide but is weaker, the mechanism of action is not completely clear, the drug has no effect on diabetes removal by the kidneys. It has been shown that the drug increases AVP secretion. Side effects cause muscle pain, weakness, increased muscle enzymes.
Increased cholesterol, hypertriglyceridemia, diabetes mellitus.
500mg 3-4 tablets / day. Contraindications: liver failure, kidney failure
Brand name, presentation, pharmacokinetics:
Tégrétol or Tegretal (Ciba-Geigy), Biston (Spofa, Tchécoslovaquie), Sirtal (Labaz). Presented in the form of tablets, 200mg content. The main indications of the drug are: epilepsy, tricyclic nerve pain, in addition the drug also contributes to reducing urination, the mechanism is not completely clear, the drug stimulates ADH secretion. An important side effect is bone marrow suppression.
Diabetes insipidus, epilepsy, pain of the tricuspid nerve. Because the drug has many side effects, the drug should only be used when other drugs cannot be used.
100-200mg twice daily. Contraindications: Allergy to drugs, pregnancy (especially the first 3 months), liver failure, hematopoietic disorders, glaucoma, urinary retention, cardiovascular disorders.
Brand name, presentation, pharmacokinetics, indications:
Dichlotride (Merck, Sharp, Dohm), Esidrex (Ciba-Geigy) ... Presented 25mg tablets. The drug is often used to increase salt and water excretion in the usual indications such as edema, hypertension, heart failure ... but the drug paradoxically reduces urination in all cases of diabetes. This effect occurs secondary to dilution of urine in the ascending arm of Henle, as well as secondary to a slight decrease in volume in the distal tubule. With the standard dosage, the drug reduces the urine urine output by 30-50% in all types of diabetes mellitus, so it is very useful when used as an adjunct to other oral medications in the treatment of central diabetes as well as diabetes. removal by the kidneys
1-5mg / kg / day. Do not use the drug in case of severe renal failure, pregnant women, nursing mothers, allergic to sulffamide, chronic gout, hyponatremia, hypokalaemia.
Some principles of treatment
Educate patients to only drink water when really thirsty. Monitoring that plasma sodium <130mEq / l appears ≥ 2 times, proving that drinking is too much for real demand.
Duration of the course:
For central diabetes in the majority of cases requiring lifelong treatment, even those cases where the cause of the disease has been eliminated, a very small number of cases improve to the point of discontinuation of treatment, usually it is not because AVP reverses hyperactivity but may be due to other more severe factors such as adrenal insufficiency, ectopic AVP secretion from a malignant tumour, severe dehydration due to dehydration disorder. However, there are reports of recovering illness so it is advisable to try stopping treatment for a few days each year to assess recovery.
Actively find the cause:
It is necessary to actively investigate the cause of the disease by many means of imaging diagnostics, cerebrospinal fluid examinations as well as hormonal exploration of the hypothalamus, anterior pituitary gland, even when the pit is calm. often.
Diabetes insipidus in pregnant women:
The only drug used is DDAVP, the dose is usually slightly higher than in non-pregnant MSM patients with the production of vasopressin’s by the placenta, 5mEq / l lower in blood sodium in pregnancy than in non-pregnant diabetics. pregnancy. DDAVP has no effect on uterine muscle contraction. It is forbidden to take oral medications to treat MSM due to teratogenicity in pregnancy.
Drink more first:
Treatment is primarily the education of the patient. Neuroleptics are ineffective for psychological intake. Limiting drinking also improves the disease, but difficult to implement, in fact the more these patients limit drinking, the thirstier they are.
Using DDAVP to urinate less but has no effect on psychological drinking, the patient continues to drink, thus always leading to water poisoning, more harmful than beneficial, manifest in 24-48 hours with hyponatremia, headache, dizziness, anxiety, nausea, vomiting, confusion, convulsions, coma, even death. An accurate diagnosis is required before deciding on treatment. If necessary, the drug can also be given at bedtime, it is necessary to consider carefully the dosage so that the drug does not prolong its effect until the next day, when the patient drinks more can cause water intoxication.