Senile diabetes insipidus

　　Diabetes insipidus is often caused by renal tubular reasons, and its specific etiology and pathogenesis are as follows:

　　First, etiology

　　1. Central diabetes insipidus (deficiency of antidiuretic hormone, neurogenic)

　　(1) Lesions in the hypothalamic-pituitary area: Various benign or malignant tumor lesions, primary such as craniopharyngioma, germ cell tumor, meningioma, pituitary adenoma, glioma, astrocytoma; secondary such as lung or breast metastatic cancer, which can also be lymphoma, leukemia, etc. Granulomatous or infectious or immune diseases, such as sarcoidosis, histiocytosis, xanthoma, encephalitis or meningitis (including tuberculous, fungal), necrotizing pituitary-neurohypophyseal inflammation, etc. Vascular or other diseases, such as Sheehan syndrome, aneurysm, thrombocytopenic purpura, brain developmental abnormalities or malformations, etc.

　　These are the most attention-worthy lesions in central diabetes insipidus, accounting for about 1/3 of central diabetes insipidus. More than 60% of these lesions are accompanied by varying degrees of hypopituitarism.

　　(2) Head injury: Head injury is often accompanied by skull fracture, but there is also a history of minor head injury, and after the onset of diabetes insipidus, MRI shows that the pituitary stalk is interrupted and locally thinned. Diabetes insipidus after cranial injury in foreign countries often occurs after traffic accidents. Diabetes insipidus may appear several years after cranial injury.

　　(3) Iatrogenic: Operations involving the hypothalamus almost always result in varying degrees of diabetes insipidus, and it is often accompanied by a decrease in anterior pituitary function before surgery. In the cases of Peking Union Medical College Hospital, an increasing number of diabetes insipidus cases have been caused by pituitary tumor surgery. Some reports indicate that surgery-induced diabetes insipidus has become the leading cause. More than half of the patients with pituitary tumor surgery develop transient and temporary diabetes insipidus, which usually disappears within 2 to 3 days. If the symptoms of diabetes insipidus persist for more than 3 weeks after surgery and do not improve, it is likely to become permanent diabetes insipidus.

　　Radiation therapy generally does not cause symptomatic diabetes insipidus, and more patients receiving radiation therapy have pituitary-hypothalamic tumor lesions.

　　(4) Idiopathic: After careful examination and excluding various intracranial lesions and systemic diseases, it is considered that there are paraventricular nucleus neurons and paraventricular nucleus antibodies in the blood of patients, which are often onset in childhood, and there are fewer cases with hypopituitarism.

　　(5) Familial: It is autosomal dominant inheritance, and some mutated genes have been found. There is a family history of disease.

　　2. Nephrogenic diabetes insipidus (antidiuretic hormone resistance or insensitivity)

　　(1) Familial: It is mostly X-linked recessive inheritance, and clinical cases are mostly in male children. There are also cases with abnormal V2 receptor genes or aquaporin II genes, or autosomal recessive inheritance.

　　(2) Acquired laterally: Many diseases or drugs in clinical practice can affect the function of renal tubules and lead to nephrogenic diabetes insipidus. Nephrogenic diabetes insipidus disappears with the cure of primary diseases, such as hypokalemia, hypercalcemia, and diabetes mellitus, etc., metabolic diseases; kidney diseases such as pyelonephritis, polycystic kidney disease; sickle cell disease or specific diseases of blood or vessels; as well as lithium, demeclocycline, and anesthetic methoxyflurane drugs.

　　3, Primary polydipsia (excessive water intake)

    These patients are all acquired due to acquired causes, such as habitual polydipsia or mental illness (schizophrenia or neurosis, decreased thirst threshold, etc.). In patients with abnormal thirst, there may be intracranial lesions such as tuberculous inflammatory granuloma, sarcoidosis, tumor, vasculitis, etc., and sometimes they coexist with central diabetes insipidus.

　　Second, pathogenesis

　　Antidiuretic hormone, also known as arginine vasopressin (AVP), is a 9-amino acid peptide substance with a molecular weight of 1084. ADH is mainly secreted by the supraoptic nucleus, and also by the paraventricular nucleus, and then transported along the descending fiber tract to the neurohypophysis for storage, and is released into the blood when needed. ADH travels with the blood to the distal renal tubules and collecting ducts, binds to cell membrane receptors, activates adenylate cyclase, increases cAMP, activates protein kinase, promotes phosphorylation of membrane proteins on the luminal surface, causing changes in the conformation of membrane proteins, and further widening the luminal side cell membrane pores, increasing the number of pores, enhancing water permeability, and promoting water reabsorption. The effects of ADH:

　　1, Regulation of water metabolism When plasma osmolality increases, it can increase the release of ADH, promoting the reabsorption of water in the distal tubules and collecting ducts, thereby reducing urine output; conversely, the release of ADH decreases, and urine output increases.

　　2, Constricting the peripheral and visceral small arteries leads to increased blood pressure, reduced return blood volume, reduced blood output, involvement of the coronary artery, and myocardial ischemia.

　　Patients with central diabetes insipidus have a partial or complete destruction of the secretion ability of antidiuretic hormone, leading to a lack or severe lack of ADH, while patients with nephrogenic diabetes insipidus have normal or slightly elevated plasma ADH levels, but the kidneys are insensitive and resistant to the action of ADH. Both of these lead to the inability to concentrate urine, increased urine output, and dehydration. The loss of body water causes a slight increase in plasma osmolality and plasma sodium levels, stimulating the thirst center to cause thirst and water intake, thereby preventing further exacerbation of dehydration. Therefore, under free water intake, neither central diabetes insipidus patients nor nephrogenic diabetes insipidus patients will experience dehydration, unless the patient has damage to the thirst mechanism or other reasons that prevent sufficient water intake to compensate for the loss of water in urine.

　　Primary polydipsia patients are different from the above two, as it is caused by excessive water intake due to the patient's habitual polydipsia, or due to mental illness, neurosis, or abnormal thirst mechanism, etc. Excessive intake of water expands the body fluid, and also slightly reduces the plasma osmolality and blood sodium levels, thereby inhibiting the secretion and release of ADH, causing dilution of urine and increased urine output to prevent further increase in body water. Therefore, the patient's low plasma osmolality and low blood sodium levels will not worsen further. After restricting water intake, the inhibition of ADH secretion in psychiatric polydipsia patients can be relieved.

　　Senile diabetes insipidus may be complicated with hypothyroidism, renal insufficiency, renal pelvis dilatation, hypokalemia, hyponatremia, water intoxication, and other conditions.

　　1, Hypothyroidism (abbreviated as hypothyroidism) is a disease characterized by a decrease in body metabolism due to a decrease in the synthesis and secretion of thyroid hormones, or insufficient physiological effects. It is classified into three types according to its etiology: primary hypothyroidism, secondary hypothyroidism, and peripheral hypothyroidism.

　　2. Renal insufficiency (renal insufficiency) is a clinical syndrome caused by severe damage to the glomeruli due to various reasons, leading to disorders in the body's excretion of metabolic waste and regulation of water and electrolyte balance, as well as acid-base balance.

　　3. When the serum K concentration

　　4. Hyponatremia only indicates that the concentration of serum sodium ions is below the normal level, which does not necessarily mean a true decrease in the body's sodium content. Depending on the acute or chronic nature of the onset, it can be divided into acute hyponatremia and chronic hyponatremia. The former refers to a decrease in serum sodium ion concentration below the normal level within 48 hours, otherwise it is chronic hyponatremia.

　　5. Water overload refers to the excessive intake or input of water, leading to water retention in the body, causing a decrease in blood osmolality and an increase in blood volume, also known as 'water intoxication' or dilutional hyponatremia. Water intoxication occurs rarely, and it is only when there is an excessive secretion of antidiuretic hormone or renal insufficiency, or when the body takes in too much water or receives excessive intravenous fluid infusion, that water accumulates in the body, leading to water intoxication.

　　The main clinical manifestations of diabetes insipidus in the elderly are polyuria, thirst, and polydipsia, with an average 24-hour urine volume of 5-10L. In severe cases, the urine volume per day and night can reach 16-24L or even up to 40L/d. The urine is colorless and clear, with similar day and night urine volumes. Regardless of day or night, urination and drinking water are required every 30-60 minutes. The urine specific gravity is low, below 1.008, closer to 1.001, and the urine osmolality is lower than that of plasma osmolality.

　　In many diseases, tertiary prevention measures are very effective in reducing the incidence of the disease. The following is a specific introduction to this method:

　　1. Primary prevention

　　Primary prevention aims to avoid the onset of diabetes insipidus. The causes of diabetes insipidus vary among different types, and taking appropriate intervention measures based on the etiology is beneficial for preventing or reducing the incidence of diabetes insipidus. For example, for patients with mental disorders or neuroses, strengthening nursing care, limiting daily water intake, and ensuring a balance between intake and output can prevent the occurrence of diabetes insipidus. Early and effective treatment of diseases such as hypokalemia, hypercalcemia, diabetes, and pyelonephritis can also be a preventive measure for renal diabetes insipidus. Some cases of renal diabetes insipidus are caused by medication, and adjusting or discontinuing medication can prevent the occurrence of diabetes insipidus. Active control of infectious diseases such as tuberculosis, syphilis, and meningitis, attention to personal safety, and avoiding head trauma can reduce the opportunities for triggering diabetes insipidus.

　　2. Secondary prevention

　　Early detection and active treatment of diabetes insipidus are secondary prevention measures. In actual practice, central diabetes insipidus is most common, with over 90% being idiopathic, postoperative or post-traumatic, or due to intracranial space-occupying lesions or infiltrative diseases. Therefore, for patients with brain surgery, brain trauma, or brain tumors, regular follow-up examinations should be conducted to detect diabetes insipidus early. Regular follow-up of individuals with a family history of diabetes insipidus can help in early detection and treatment of polyuria and polydipsia, thus achieving early detection and treatment of diabetes insipidus.

　　3. Third-level Prevention

　　The third level of prevention focuses on preventing the occurrence of severe complications. Patients with diabetes insipidus may have polyuria for a long time, which can lead to bladder dilation, hydronephrosis of the ureters and renal pelvis. Some patients may develop dehydration, damage to the central nervous system, due to limited water intake or lack of thirst sensation. Patients with diabetes insipidus caused by pituitary-hypothalamic tumors or infiltrative lesions, in addition to dehydration, may also have hypopituitarism, tumor compression symptoms, increased intracranial pressure, and a high mortality rate. When diabetes insipidus is combined with hypopituitarism, it is often triggered by infection, diarrhea, vomiting, dehydration, hunger, cold, heatstroke, surgery, trauma, anesthesia, alcoholism, and the use of sedative-hypnotics, hypoglycemic drugs, and can lead to pituitary crisis. Symptoms may include abnormal body temperature (elevated or low body temperature), hypoglycemia, circulatory failure, respiratory failure, water intoxication, and in severe cases, coma and convulsions, which can be life-threatening. Therefore, early detection of diabetes insipidus and early antidiuretic treatment, treatment of the primary disease, treatment of various complications, control of various triggering factors can reduce the occurrence of the above complications, improve the quality of life, and prolong the life of patients.

　　Generally, elderly patients with diabetes insipidus do not need to undergo the following examination items for diagnosis:

　　1. Urine Specific Gravity Determination

　　Determine urine specific gravity from any urine sample, and urine specific gravity in central and renal diabetes insipidus.

　　2. Plasma and Urine Osmolality Determination

　　In central and renal diabetes insipidus, plasma osmolality may be higher than normal, and urine osmolality is often less than plasma osmolality. In some cases of partial diabetes insipidus, urine osmolality can exceed plasma osmolality but is less than 600mmol/L. For patients with psychogenic polydipsia, plasma osmolality may be slightly lower.

　　3. Water Deprivation Vasopressin Test

　　This experiment should be conducted under strict observation. Before water deprivation, measure body weight, blood pressure, urine volume, urine specific gravity, and urine osmolality. The period of water deprivation is 10 to 14 hours. During water deprivation, urinate once every 2 hours, and measure urine volume, urine specific gravity, and urine osmolality. Measure body weight and blood pressure every hour. When the urine osmolality reaches the peak plateau, that is, the difference between the osmolality of two consecutive urine samples.

　　4. Hypertonic Saline Test

　　Prepare a 2.5% hypertonic saline solution with physiological saline or injection water, 10% NaCl, and prepare 10U of posterior pituitary extract. The water intake is 20ml/kg body weight, which should be evenly consumed within 1 hour. Urine collection should start 30 minutes after drinking, with one collection every 15 minutes. After two consecutive urine collections with a flow rate of 5ml/min or more, 0.25ml/(min·kg) of 2.5% hypertonic saline should be administered intravenously for 45 minutes. Urine collection should continue every 15 minutes after the start of infusion. If there is no significant reduction in urine volume 30 minutes after the completion of hypertonic saline infusion, 5U of posterior pituitary extract can be administered subcutaneously, with urine collection twice every 15 minutes after injection.

　　5. Nicotine Test

　　早晨空腹饮水20ml/kg体重，尽量均匀在20min内饮完，饮水后每15min留尿，如连续2次尿量5ml/min以上，则吸烟者3支，不吸烟者2支香烟，30min内吸完，吸烟后连续留尿4次，测尿量、尿渗透压，吸烟前后采血，测血浆渗透压、血浆AVP。

　　In the morning, drink 20ml/kg body weight of water on an empty stomach, try to drink evenly within 20 minutes, and collect urine every 15 minutes after drinking water. If the urine volume is 5ml/min or more for two consecutive times, smoke 3 cigarettes within 30 minutes for smokers, and 2 cigarettes for non-smokers, and collect urine for 4 consecutive times after smoking. Measure urine volume and urine osmolality, and collect blood before and after smoking to measure plasma osmolality and plasma AVP.

　　After normal individuals smoke, the urine volume decreases to less than 25% of the control, and the urine osmolality exceeds the plasma osmolality. The individual differences in response are large, and the plasma AVP concentration may exceed 50 pg/ml in some patients, but some patients may not have a response. In complete diabetes insipidus, the decrease in urine volume is not obvious, and the urine osmolality is lower than the plasma osmolality. In patients with psychogenic polydipsia, the urine osmolality may exceed the plasma osmolality. In patients with adrenal cortical insufficiency, as with the hypertonic saline test, 30mg of oral hydrocortisone acetate is taken 4 hours before drinking water before the test.

　　Nicotine can directly stimulate neurons to release AVP, theoretically it can distinguish whether the osmoreceptor is damaged or the neuron is damaged, but it has no practical significance, and it has side effects such as nausea, vomiting, dizziness, pallor, blood pressure drop, and glomerular filtration rate drop, and is now not used.

　　6. Arginine Vasopressin Measurement

　　Plasma levels can be measured by radioimmunoassay, which can be determined at any time or after water deprivation. The normal plasma AVP (drinking freely) is 2.3-7.4 pmol/L, which can increase significantly after water deprivation. In patients with central diabetes insipidus, the plasma arginine vasopressin level does not increase after water deprivation, while in patients with psychogenic polydipsia and renal diabetes insipidus, the plasma arginine vasopressin level is significantly increased.

　　Dietary taboos for patients with senile diabetes insipidus

　　For the treatment of senile diabetes insipidus, there are currently two commonly used treatment methods:

　　1. Hormone replacement therapy

　　When patients can no longer secrete and release AVP, i.e., in complete diabetes insipidus, hormone replacement therapy is required. Since diabetes insipidus is generally a lifelong disease, long-term medication is needed, and desmopressin DDAVP is the best choice, and oral tablets have been widely used in China.

　　1. Pituitary posterior lobe water solution: The common dose is 5 to 10 U, administered by subcutaneous injection. The action time is 3 to 6 hours. Due to its short action time, it is currently used for perioperative and unconscious patients, as well as for trials. Long-term use requires injection 3 to 4 times a day, which is very inconvenient.

　　2. Pituitary posterior lobe powder nasal inhaler 'Diabetes Stop': Administered by nasal application or inhalation, the dose is 30 to 40 mg per time, with an action time of 5 to 8 hours. The disadvantages are that long-term use causes atrophy of the nasal mucosa and loss of efficacy, and brings pain caused by atrophy of the nasal mucosa, which is not suitable for long-term use and can be used for short-term use during travel or business trips.

　　3. Lysine vasopressin: It is an artificial synthetic agent used for nasal spray, with an action time of 4 to 5 hours. The disadvantages are the same as those of the pituitary posterior lobe powder nasal inhaler 'Diabetes Stop'.

　　4. Ointment tannic acid vasopressin long-acting pituitary posterior lobe powder nasal inhaler 'Diabetes Stop': It is a suspension, which should be shaken well before use, and should be warmed before use in cold weather. It is administered by deep intramuscular injection, with a single dose of 0.1 to 0.5 ml (100 mg/5 ml). The antidiuretic effect can last for 1 to 5 days depending on the amount. Treatment should start with a small dose of 0.05 to 0.1 ml, and gradually increase to the required amount. It is usually administered twice a week. The disadvantages include difficulty in absorption, easy formation of hard nodules at the injection site, or irregular absorption. Additionally, within 2 to 3 days after the first injection, symptoms such as headache, nausea, anorexia, drowsiness, or irritability may occur, which are symptoms of water intoxication caused by excessive water retention. Some patients have become accustomed to polydipsia and continue to drink large amounts of water during treatment, which can also easily cause water intoxication. Sensitive patients may have vascular constriction reactions such as abdominal pain, pale complexion, and increased blood pressure. Some patients may experience allergic reactions such as rashes, which require discontinuation of the drug.

　　5. The most ideal treatment is desmopressin acetate DDAVP: It is a water-based drug of synthetic vasopressin analogs, administered by nasal drops, with a dosage that varies greatly from person to person, ranging from 5 to 20 pg per day by nasal drops. The antidiuretic effect can last for 12 hours or longer. In China, there is an oral desmopressin DDAVP tablet called 'Mingning', and the treatment dose needs to be individualized. Oral tablets are more convenient in terms of use, carrying, and storage compared to nasal sprays and injections. Desmopressin DDAVP increases the antidiuretic activity by nearly 3 times by deaminating the N-terminal glutamine of the natural arginine antidiuretic hormone, replacing the left-handed arginine at position 8 with dextrorotary arginine, which reduces the vasoconstrictive effect by 400 to 800 times, and strengthens the stability in the blood, extends the duration of antidiuretic effect, thus significantly improving the antidiuretic effect while actually having no vasoconstrictive effect, and reducing side effects with long-term use. Regular monitoring of plasma osmolality is required after the start of treatment, initially once every 1 to 2 weeks, then once every 3 months, to observe whether the dosage used is appropriate. The drug has very few side effects, and it is reported that mild and transient gastrointestinal discomfort may occur.

　　Secondly, the treatment of non-hormonal antidiuretic drugs.

　　Patients with mild central diabetes insipidus, that is, partial diabetes insipidus with some residual AVP release, can have a therapeutic response to several non-hormonal preparations.

　　1. Chlorpropamide is an oral hypoglycemic agent, stimulates AVP release from the brain nerve pituitary, increases the sensitivity of renal tubules to AVP, and makes urine concentrated, so it can be used for patients who can still secrete part of ADH, with a dose of 0.2-0.5g/d, once a day, with sufficient antidiuretic effect. Because its effect lasts for 24 hours, there is a possibility of hypoglycemia, especially in elderly patients and those with heart and kidney failure, the action time is prolonged. The number of users in China has decreased in recent years.

　　2. Clofibrate antiphlogistic, has the effect of stimulating AVP secretion, and can also be used for partial central diabetes insipidus, with a dose of 1.0-2.0g/d, the action time lasts for 24h, and there is often a persistent antidiuretic effect. In some cases, when used in combination with chlorpropamide, it can lead to complete recovery of water regulation and satisfactory control of polyuria symptoms. Adverse reactions include indigestion, abdominal distension, muscle pain, and liver damage.

　　3. Carbamazepine amide imide, can stimulate AVP release and produce antidiuretic effect, effective dose 400-600mg/d. However, long-term use of this drug can cause adverse reactions such as liver damage, blood count suppression, and headache, and is not widely used. The duration of continuous medication should not be too long.

　　4. Hydrochlorothiazide dihydrochlorothiazide.