bubble_chart Overview

Diabetes insipidus refers to a group of symptoms caused by either insufficient secretion of vasopressin (VP), also known as antidiuretic hormone (ADH) (referred to as central or pituitary diabetes insipidus), or a defect in the kidney's response to vasopressin (referred to as nephrogenic diabetes insipidus). Its characteristics include polyuria, polydipsia, low specific gravity urine, and hypotonic urine.

bubble_chart Etiology

1. Primary (idiopathic or of unknown cause) diabetes insipidus: accounts for approximately 1/3 to 1/2 of cases. It typically begins in childhood and is rarely (<20%) associated with anterior pituitary dysfunction. This diagnosis can only be confirmed after a thorough search for secondary causes has been ruled out. When anterior pituitary dysfunction, hyperprolactinemia, or radiological evidence of intrasellar or suprasellar lesions with a deteriorated pattern is present, every effort should be made to identify the cause. The longer the follow-up period without identifying a primary factor, the more certain the diagnosis of primary diabetes insipidus becomes. Reports indicate that patients with primary diabetes insipidus have reduced neurons in the supraoptic and paraventricular nuclei and the presence of antibodies against hypothalamic nuclei in circulation.
2. Secondary diabetes insipidus: occurs due to neoplastic or invasive lesions in the hypothalamus or pituitary, including chromophobe adenoma, craniopharyngioma, germinoma, pinealoma, glioma, meningioma, metastatic tumors, leukemia, histiocytosis, granulomatous tumors, xanthoma, sarcoidosis, and infectious diseases of the brain (such as subcutaneous nodules, syphilis, and vascular disorders).
3. Hereditary diabetes insipidus: Hereditary diabetes insipidus is very rare and may present as an isolated genetic defect or as part of the DIDMOAD syndrome (characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, also known as Wolfram syndrome).
4. Physical injury: Commonly seen after brain surgery, particularly involving the pituitary or hypothalamus, following radioactive isotope therapy, or after severe head trauma. Diabetes insipidus caused by surgery usually appears 1–6 days post-operation and resolves within a few days. After an interval of 1–5 days, the symptoms may permanently disappear or recur and become chronic. Severe head trauma, often accompanied by skull fractures, may lead to diabetes insipidus, with a minority of patients also experiencing anterior pituitary dysfunction. Trauma-induced diabetes insipidus may resolve spontaneously, though in some cases, it may take up to 6 months to fully disappear.
5. Diabetes insipidus symptoms may appear during pregnancy and resolve within a few days after childbirth. Sheehan’s syndrome may manifest diabetes insipidus symptoms after treatment with cortisone. Pregnancy can also lead to AVP-resistant diabetes insipidus, likely due to elevated levels of placental vasopressinase in circulation. In these patients, plasma AVP levels are elevated, and they show no response to high-dose AVP but respond to desmopressin treatment, with symptom relief after childbirth.

bubble_chart Pathogenesis

1. Physiology of Vasopressin

(1) Synthesis and Metabolism of AVP Vasopressin is synthesized in the neurons of the supraoptic and paraventricular nuclei of the hypothalamus. Its initial product is the preprohormone, which enters the Golgi apparatus to form the prohormone. The latter is encapsulated in neurosecretory vesicles. These vesicles travel along the axons of the hypothalamo-neurohypophyseal tract to the neurohypophysis. During this process, enzymatic action produces the active nonapeptide, arginine vasopressin (AVP), along with a molecular-weight protein (neurophysin) and a glycopeptide composed of 39 amino acids. All three products are released into the peripheral blood. After secretion by hypothalamic neurons, AVP descends along the hypothalamo-neurohypophyseal tract to the terminals, where it is stored in the neurohypophysis. In recent years, AVP fibers have also been found in the lateral zone of the median eminence. AVP can also be secreted into the pituitary portal system, as well as in areas such as the floor of the third ventricle and the vasomotor centers of the brainstem.

AVP binds to endothelial cells in the distal convoluted tubules and collecting ducts of the kidneys, promoting water flow from the tubular lumen to the interstitium, thereby helping to maintain osmotic pressure and fluid volume homeostasis. The concentration of AVP in plasma is very low and does not exhibit vasoactive effects, but high concentrations of AVP acting on V1 receptors can cause vasoconstriction. AVP present in brain axons may be involved in learning and memory processes, while AVP fibers in the median eminence may be associated with promoting ACTH release.

The concentration of AVP in plasma and urine can be measured by immunoassay. Under conditions of unrestricted fluid intake, the neurohypophysis contains approximately 6 units or 18 mmol (20 μg) of AVP, with peripheral blood AVP concentrations ranging from 2.3 to 7.4 pmol/L (2.5–8 ng/L). Blood AVP levels vary diurnally, peaking late at night and early in the morning and reaching their lowest levels in the afternoon. Under normal hydration conditions, healthy individuals release 23–1400 pmol (400–1500 ng) of AVP from the pituitary over 24 hours, while excreting 23–80 pmol (25–90 ng) of AVP in urine. After 24–48 hours of water deprivation, AVP release increases 3–5 times, with sustained increases in blood and urine levels. AVP is primarily inactivated in the liver and kidneys, with about 7–10% excreted in urine in its active form.

(2) Regulation of AVP Release

1. Osmoreceptors AVP release is influenced by various stimuli. Under normal conditions, AVP release is primarily regulated by osmoreceptors in the hypothalamus, with changes in osmotic pressure stimulating AVP production and release. The feedback regulation mechanism between plasma osmotic pressure and AVP release maintains plasma osmotic pressure within a narrow range. After administering a water load of 20 ml/kg to healthy individuals, the average plasma osmotic pressure is 281.7 mOsm/kg·H₂O. Following the injection of hypertonic saline in individuals given a water load, the plasma osmotic pressure is 287.3 mOsm/kg·H₂O.

2. Volume Regulation A decrease in blood volume stimulates stretch receptors in the left atrium and pulmonary veins, reducing inhibitory stretch impulses from baroreceptors to the hypothalamus and thereby stimulating AVP release. Additionally, factors such as shouting, standing upright, or vasodilation due to a warm environment can activate this mechanism to restore blood volume. Volume depletion can increase circulating AVP concentrations to 10 times the levels induced by hyperosmolarity.

3. Baroreceptors Hypotension stimulates carotid and aortic baroreceptors, triggering AVP release. Hypotension caused by blood loss is the most potent stimulus, significantly increasing plasma AVP concentrations and leading to vasoconstriction until blood volume and pressure are restored.

4. Neuroregulation Many neurotransmitters and neuropeptides in the hypothalamus have the function of regulating AVP release. For example, acetylcholine, angiotensin II, histamine, bradykinin, γ-neuropeptide, etc., can all stimulate AVP release. With increasing age, the responsiveness of AVP to elevated plasma osmolality increases, and plasma AVP levels progressively rise. These physiological changes may increase the risk of water retention and hyponatremia in the elderly.

5. Drug Effects Drugs that can stimulate AVP release include nicotine, morphine, vincristine, cyclophosphamide, clofibrate, chlorpropamide, and certain tricyclic antidepressants. Ethanol exerts a diuretic effect by inhibiting neurohypophyseal function. Phenytoin and chlorpromazine can inhibit AVP release, thereby producing a diuretic effect.

(3) AVP Response to Water Deprivation and Water Load Water deprivation increases osmotic pressure, stimulating antidiuretic hormone release. The maximum urine osmotic pressure after water deprivation varies with renal medullary osmotic pressure and other intrarenal factors. In normal individuals, after 18–24 hours of water deprivation, plasma osmotic pressure rarely exceeds 292 mOsm/kg·H₂O. Plasma AVP concentration increases to 14–23 pmol/L (15–25 ng/L). Water intake can suppress AVP release. After a water load of 20 ml/kg in normal individuals, plasma osmotic pressure decreases to an average of 281.7 mOsm/kg·H₂O.

(4) Relationship Between AVP Release and Thirst Under normal conditions, AVP release and the sensation of thirst are coordinated, both triggered by grade I increases in plasma osmotic pressure. When plasma osmotic pressure rises above 292 mOsm/kg·H₂O, the sensation of thirst becomes increasingly pronounced, prompting water intake only when urine concentration reaches its maximum limit. Thus, under normal circumstances, grade I hypernatremia due to water loss enhances thirst, increasing fluid intake to restore and maintain normal plasma osmotic pressure. Conversely, when thirst is impaired, fluid loss cannot be promptly corrected by drinking, and hypernatremia may occur despite maximal AVP-induced urine concentration.

(5) Role of Glucocorticoids Glucocorticoids and AVP have antagonistic effects on water excretion. Cortisone can raise the osmotic threshold for AVP release induced by hypertonic saline infusion in normal individuals. Glucocorticoids can prevent water intoxication and correct abnormal responses to water loading in adrenal insufficiency. In adrenal insufficiency, impaired urinary dilution may be partly due to excessive circulating AVP, but glucocorticoids can also directly act on renal tubules to reduce water permeability, increasing free water excretion in the absence of AVP.

(6) Cellular Mechanism of AVP Action The mechanism of AVP action on renal tubules: ① AVP binds to V2 receptors on the basolateral membrane of renal tubular cells; ② The hormone-receptor complex activates adenylate cyclase via stimulatory G proteins; ③ Increased generation of cyclic AMP (cAMP); ④ cAMP translocates to the luminal membrane, activating membrane-bound protein kinases; ⑤ Protein kinases induce phosphorylation of membrane proteins; ⑥ Increased luminal membrane permeability to water enhances water reabsorption. Many ions and drugs can influence AVP action. Calcium and lithium inhibit adenylate cyclase response to AVP and also suppress cAMP-dependent protein kinases. Conversely, chlorpropamide enhances AVP-induced adenylate cyclase activation.

2. Dysfunction at any stage of AVP production and release can lead to the onset of the disease. By comparing changes in plasma and urine osmolality under normal water intake, water loading, and water deprivation, central diabetes insipidus can be classified into four types: ① Type 1: During water deprivation, plasma osmolality increases significantly, but urine osmolality rarely rises, and no AVP is released upon hypertonic saline injection. This type indeed exhibits AVP deficiency. ② Type 2: During water deprivation, urine osmolality suddenly increases, but there is no osmotic threshold upon saline injection. These patients lack an osmotic sensing mechanism, and AVP release is only stimulated by severe dehydration leading to hypovolemia. ③ Type 3: As plasma osmolality rises, urine osmolality increases slightly, and the AVP release threshold is elevated. These patients have a sluggish AVP release mechanism or reduced osmoreceptor sensitivity. ④ Type 4: Both plasma and urine osmolality curves shift to the right of normal. In these patients, AVP release begins at normal plasma osmolality, but the release amount is below normal. Patients with types ② to ④ show a good antidiuretic response to nausea, nicotine, acetylcholine, chlorpropamide, and clofibrate, indicating that AVP synthesis and storage are intact and release occurs under appropriate stimulation. In rare cases, patients with types ② to ④ may present with asymptomatic hypernatremia and very mild or even no evidence of diabetes insipidus.

bubble_chart Clinical Manifestations

Pituitary diabetes insipidus can occur at any age, usually manifesting in childhood or early adulthood, with a higher prevalence in males than females, at a ratio of approximately 2:1. The onset date is generally clear. Most patients exhibit polydipsia, excessive thirst, and polyuria. Nocturia is particularly noticeable, with a relatively fixed daily urine output, typically exceeding 4L/day and rarely surpassing 18L/day, although cases of up to 40L/day have been reported. The urine specific gravity is <1.006，部分性尿崩症在嚴重脫水時可達1.010。尿滲透壓多數<200mOsm/kg﹒H₂O. Thirst is often severe, and in individuals with a normally functioning thirst center, fluid intake roughly equals output. Generally, patients with diabetes insipidus prefer cold drinks. If water intake is unrestricted, it primarily affects sleep and causes physical weakness. Intellectual and physical development are nearly normal. Excessive thirst and polyuria may worsen with fatigue, infection, menstruation cycles, or pregnancy. Hereditary diabetes insipidus begins in early childhood, and due to underdevelopment of the thirst center, it can lead to dehydration fever and hypernatremia. When tumors or craniocerebral trauma surgery affects the thirst center, hypernatremia (manifesting as delirium, convulsions, vomiting, etc.) may occur alongside localized symptoms. Interestingly, when diabetes insipidus coexists with anterior pituitary insufficiency, the symptoms of diabetes insipidus may actually lessen, only to reappear or worsen after glucocorticoid replacement therapy.

bubble_chart Auxiliary Examination

1. Evaluation of the Relationship Between Plasma Osmolality and Urine Osmolality The normal relationship between plasma osmolality and urine osmolality. If a polyuric patient's repeated simultaneous measurements of plasma and urine osmolality fall to the right of the shaded area, the patient may have central diabetes insipidus or nephrogenic diabetes insipidus. If the response to vasopressin injection is below normal (see the water deprivation test below) or if the blood or urine AVP concentration increases, the diagnosis is nephrogenic diabetes insipidus. The relationship between plasma and urine osmolality is particularly useful, especially after neurosurgery or head trauma, as it can quickly differentiate diabetes insipidus from excessive parenteral fluid administration. For these patients, intravenous fluids can be temporarily slowed, and repeated measurements of hematuria osmolality can be taken.

2. Water Deprivation Test Comparing urine osmolality after water deprivation and after vasopressin administration is a simple and practical method to confirm diabetes insipidus and differentiate vasopressin deficiency from other causes of polyuria. This test is often used in conjunction with the osmolality relationship (15-21) to evaluate urine osmolality.

**Principle:** In normal individuals, water deprivation increases plasma osmolality and reduces circulating blood volume, both of which stimulate AVP release, leading to decreased urine output, increased urine specific gravity, and elevated urine osmolality, with little change in plasma osmolality.

**Method:** Water deprivation lasts 6–16 hours (typically 8 hours), depending on the severity of the condition. Before the test, measure body weight, blood pressure, plasma osmolality, and urine specific gravity. Subsequently, collect urine hourly to measure urine volume, specific gravity, and osmolality. When urine volume stabilizes (with consecutive measurements showing minimal change) and urine osmolality changes by <30 mOsm/kg·H₂O, endogenous AVP secretion has reached its maximum (mean). At this point, measure plasma osmolality and immediately administer 5 units of aqueous vasopressin subcutaneously. Then collect urine to measure urine volume and osmolality 1–2 more times.

**Results Analysis:** - **Normal individuals:** After water deprivation, body weight, blood pressure, and plasma osmolality change little (<295 mOsm/kg·H₂O), and urine osmolality can exceed 800 mOsm/kg·H₂O. After vasopressin injection, urine osmolality increases by no more than 9%. - **Psychogenic polydipsia:** Results are similar to or close to those of normal individuals. - **Central diabetes insipidus:** After water deprivation, weight loss exceeds 3%. Severe cases may show symptoms like hypotension and dysphoria. Depending on severity, it can be classified as partial or complete diabetes insipidus: - **Partial diabetes insipidus:** Plasma osmolality plateau does not exceed 300 mOsm/kg·H₂O, and urine osmolality may slightly exceed plasma osmolality. After vasopressin injection, urine osmolality continues to rise. - **Complete diabetes insipidus:** Plasma osmolality plateau exceeds 300 mOsm/kg·H₂O, and urine osmolality remains below plasma osmolality. After vasopressin injection, urine osmolality increases by over 9%, sometimes even doubling. - **Nephrogenic diabetes insipidus:** Urine cannot concentrate after water deprivation, and there is no response to vasopressin injection.

**Test Characteristics:** This method is simple, reliable, and widely used. Side effects include vasopressin-induced hypertension, which may trigger angina, abdominal pain, uterine contractions, etc.

3. Hypertonic Saline Test This test is rarely used for diagnosing diabetes insipidus. It is employed to demonstrate changes in the osmotic threshold for AVP release and has some value in analyzing certain hyponatremic or hypernatremic conditions.

4. Plasma AVP Measurement In partial diabetes insipidus and psychogenic polydipsia, long-term polyuria leads to medullary washout, reducing the osmotic gradient and impairing renal responsiveness to endogenous AVP. This makes it difficult to differentiate from partial nephrogenic diabetes insipidus. Simultaneous measurement of plasma AVP, plasma osmolality, and urine osmolality during a water deprivation test can aid in differential diagnosis.

5. Etiological diagnosis of central diabetes insipidus Once central diabetes insipidus is diagnosed, further etiological diagnosis must be conducted. Tests such as visual acuity, visual field examination, sella turcica radiography, sella CT, and MRI should be performed to determine the etiology.

bubble_chart Diagnosis

The diagnosis of diabetes insipidus can be made by measuring plasma and urine osmolality, a reliable and safe method that allows clinicians to quickly diagnose and initiate treatment.

bubble_chart Treatment Measures

(1) Aqueous Vasopressin  Diabetes insipidus can be treated with hormone replacement therapy. Vasopressin is ineffective when taken orally. Subcutaneous injection of 5–10U of aqueous vasopressin provides an effect lasting 3–6 hours. This preparation is commonly used for the initial treatment of diabetes insipidus patients with impaired consciousness secondary to traumatic brain injury or neurosurgical procedures. Due to its short duration, it helps identify the recovery of neurohypophyseal function and prevents water intoxication in patients receiving intravenous fluids.

(2) Powdered Diabetes Insipidus Treatment  Lysine vasopressin is a nasal spray that provides an antidiuretic effect lasting 4–6 hours per dose. In cases of respiratory infections or allergic rhinitis, nasal mucosal edema reduces absorption of this medication. Under such circumstances, or in unconscious diabetes insipidus patients, desmopressin should be administered subcutaneously.

(3) Long-Acting Diabetes Insipidus Treatment  Long-acting diabetes insipidus treatment is a tannate vasopressin preparation containing 5U per milliliter. Starting from 0.1ml, the dose can be gradually increased to 0.5–0.7ml per injection based on daily urine output, with effects lasting 3–5 days. Administer via deep intramuscular injection. Ensure thorough mixing before injection and avoid overdose to prevent water intoxication.

(4) Synthetic DDAVP (1-Desamino-8-D-Arginine Vasopressin, Desmopressin)  DDAVP enhances antidiuretic effects while its vasoconstrictive action is only 1/400 that of AVP, with an antidiuretic-to-pressor ratio of 4000:1. Its effects last 12–24 hours, making it the most ideal antidiuretic currently available. Subcutaneous injection of 1–4μg or intranasal administration of 10–20μg provides most patients with 12–24 hours of antidiuretic effect.

(5) Other Oral Medications  Diabetes insipidus patients with residual AVP release function may respond to certain non-hormonal oral medications. Chlorpropamide stimulates pituitary AVP release and enhances AVP’s effect on renal tubules, possibly by increasing tubular cAMP formation, but it is ineffective in nephrogenic diabetes insipidus. A dose of 200–500mg once daily exerts an antidiuretic effect, beginning hours after absorption and lasting 24 hours. Chlorpropamide can restore thirst sensation, benefiting patients with hypodipsia. Although it has hypoglycemic effects, timely meals can prevent hypoglycemia. Other side effects include hepatotoxicity and leukopenia. The mechanism of hydrochlorothiazide’s antidiuretic effect is unclear. Initially, it acts as a saluretic, causing grade I salt depletion and reducing extracellular fluid, thereby increasing proximal tubule water reabsorption and decreasing initial urine volume entering the distal tubule. The exact mechanism remains unknown. It is also effective in nephrogenic diabetes insipidus, reducing urine output by about 50%. Synergistic effects occur when combined with chlorpropamide. The dose is 50–100mg/day, taken in divided doses. A low-salt diet is recommended during treatment, and consumption of coffee beans or cocoa-based products should be avoided. Clofibrate stimulates AVP release and can also treat diabetes insipidus at 100–500mg, 3–4 times daily. Side effects include liver damage, myositis, and gastrointestinal reactions. Carbamazepine may also exert antidiuretic effects by stimulating AVP release, with an effective dose of 400–600mg daily. However, due to other toxic side effects, it is not widely used.

Secondary diabetes insipidus should first be managed by treating the underlying cause. If a cure is not possible, the aforementioned medications may be used.

bubble_chart Differentiation

Diabetes insipidus must be differentiated from other types of polyuria. Some can be distinguished through medical history (such as recent use of lithium or mannitol, surgery under methoxyflurane anesthesia, or recent kidney transplantation). In other patients, physical examination or simple laboratory tests will suggest the diagnosis (e.g., diabetes mellitus, kidney disease, sickle cell anemia, hypercalcemia, hypokalemia, primary hyperaldosteronism).

Congenital nephrogenic diabetes insipidus is a rare form of polyuria caused by unresponsiveness to AVP. Females are less severely affected than males and can concentrate urine during water deprivation, responding to high doses of desmopressin. In one family with this condition, an abnormal gene was found on the short arm of the X chromosome. Most patients have V2 receptor abnormalities, while some exhibit post-receptor defects. All patients have normal V1 receptor function. When nephrogenic diabetes insipidus cannot be distinguished from central diabetes insipidus through osmolality measurements, elevated blood or urine AVP levels relative to plasma osmolality can confirm the diagnosis of nephrogenic diabetes insipidus.

Primary polydipsia or psychogenic polydipsia is sometimes difficult to differentiate from diabetes insipidus, and both forms may coexist. Chronic excessive water intake leads to hypotonic polyuria, which can be confused with diabetes insipidus. Intermittent excessive water intake, even with normal urine dilution capacity, can cause water intoxication and dilutional hyponatremia. This phenomenon is rare, but these patients have an increased tendency toward hyponatremia. Their polydipsia and polyuria are often unstable and typically lack nocturnal polyuria, unlike the persistent polyuria of diabetes insipidus. The diagnosis of primary polydipsia is confirmed by low plasma osmolality and hypotonicity, with normal or often above-normal relationships. During a water deprivation test, urine osmolality stabilizes, and there is little or no increase in urine osmolality after vasopressin injection. Chronic high water intake suppresses AVP release, and prolonged polyuria leads to loss of the renal medullary osmotic gradient, causing urine osmolality to be lower than normal relative to blood osmolality. Therefore, it can sometimes be challenging to distinguish primary polydipsia from partial central diabetes insipidus, and some patients may exhibit both conditions.