DIABETES INSIPIDUS

The neurohypophysis, or posterior pituitary gland, is formed by axons that originate in large cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus. It produces two hormones: (1) arginine vasopressin (AVP), also known as antidiuretic hormone; and (2) oxytocin

In the absence of AVP, these cells are impermeable to water and reabsorb little, if any, of the relatively large volume of dilute filtrate that enters from the proximal nephron. This results in the excretion of very large volumes (as much as 0.2 mL/kg per min) of maximally dilute urine (specific gravity and osmolarity ~1.000 and 50 mosmol/L, respectively), a condition known as a water diuresis. AVP action is mediated via binding to G protein–coupled V₂ receptors on the serosal surface of the cell, activation of adenyl cyclase, and insertion into the luminal surface of water channels composed of a protein known as aquaporin 2. At high concentrations, AVP also causes contraction of smooth muscle in blood vessels and in the gastrointestinal tract, induces glycogenolysis in the liver, and potentiates adrenocorticotropic hormone (ACTH) release by corticotropin-releasing factor. These effects are mediated by V_1a or V_1b receptors that are coupled to phospholipase C.

control is mediated by specialized hypothalamic cells, known as osmoreceptors, which are extremely sensitive to small changes in the plasma concentration of sodium and certain other solutes but are insensitive to other solutes such as urea or glucose. The osmoreceptors appear to include inhibitory as well as stimulatory components that function in concert to form a threshold, or set point, control system for AVP release; the average threshold, or set point, for AVP release corresponds to a plasma osmolarity or sodium of about 280 mosmol/L or 135 meq/L, respectively; levels only 2–4% higher normally result in maximum antidiuresis. Though relatively stable in a healthy adult, the set of the osmoregulatory system can also be lowered by pregnancy, the menstrual cycle, estrogen, and relatively large, acute reductions in blood pressure or volume.

The effects of acute changes in blood volume or pressure are mediated largely by neuronal afferents that originate in transmural pressure receptors of the heart and large arteries and project via the vagus and glossopharyngeal nerves to the brain stem, from whence postsynaptic projections ascend to the hypothalamus.

AVP secretion can also be stimulated by nausea, acute hypoglycemia, glucocorticoid deficiency, smoking, and, possibly, hyperangiotensinemia. The emetic stimuli are extremely potent since they typically elicit immediate, 50- to 100-fold increases in plasma AVP, even when the nausea is transient and unassociated with vomiting or other symptoms.

During pregnancy, the metabolic clearance of AVP is increased three- to fourfold due to placental production of an N-terminal peptidase.

thirst osmostat appears to be "set" about 5% higher than the AVP osmostat. This arrangement ensures that thirst, polydipsia, and dilution of body fluids do not occur until plasma osmolarity/sodium start to exceed the defensive capacity of the antidiuretic mechanism.

Oxitocina: it has relatively little antidiuretic effect and seems to act mainly on mammary ducts to facilitate milk letdown during nursing. It may also help to initiate or facilitate labor by stimulating contraction of uterine smooth muscle, but it is not yet clear if this action is physiologic or necessary for normal delivery.

Diabetes insipidus

Clinica: Decreased secretion or action of AVP usually manifests as DI, a syndrome characterized by the production of abnormally large volumes of dilute urine. The 24-h urine volume is >50 mL/kg body weight and the osmolarity is <300>. The polyuria produces symptoms of urinary frequency, enuresis, and/or nocturia, which may disturb sleep and cause mild daytime fatigue or somnolence. It is also associated with thirst and a commensurate increase in fluid intake (polydipsia). Clinical signs of dehydration are uncommon unless fluid intake is impaired.

Deficient secretion of AVP can be primary or secondary. The primary form usually results from agenesis or irreversible destruction of the neurohypophysis and is variously referred to as neurohypophyseal DI, pituitary DI, or central DI. It can be caused by a variety of congenital, acquired, or genetic disorders but almost half the time it is idiopathic . The genetic form of neurohypophyseal DI is usually transmitted in an autosomal dominant mode and is caused by diverse mutations in the coding region of the AVP–neurophysin II (or AVP-NPII) gene. The AVP deficiency and DI develop several months to several years after birth and appear to result from selective degeneration of AVP-producing magnocellular neurons, probably caused by accumulation of misfolded precursor. An autosomal recessive form due to an inactivating mutation in the AVP portion of the gene, an X-linked recessive form due to an unidentified gene on Xq28, and an autosomal recessive form due to mutations of the WFS 1 gene responsible for Wolfram's syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and neural deafness; DIDMOAD.

Secondary deficiencies of AVP result from inhibition of secretion by excessive intake of fluids. They are referred to as primary polydipsia and can be divided into three subcategories. One of them, called dipsogenic DI, is characterized by inappropriate thirst caused by a reduction in the "set" of the osmoregulatory mechanism. It sometimes occurs in association with multifocal diseases of the brain such as neurosarcoid, tuberculous meningitis, or multiple sclerosis but is often idiopathic. The second subtype, called psychogenic polydipsia, is not associated with thirst, and the polydipsia seems to be a feature of psychosis. The third subtype, which may be referred to as iatrogenic polydipsia, results from recommendations to increase fluid intake for its presumed health benefits.

Physiopathology

When the secretion or action of AVP is reduced below 80–85% of normal, urine concentration ceases and the rate of output increases to symptomatic levels, the polyuria results in a small (1–2%) decrease in body water and a commensurate increase in plasma osmolarity and sodium concentration that stimulate thirst and a compensatory increase in water intake. The severity of the antidiuretic defect varies markedly among patients with pituitary, gestational, or nephrogenic DI.

In the dipsogenic form of primary polydipsia, fluid intake is excessive because the osmotic threshold for thirst appears to be reset to the left, often well below that for AVP release. When deprived of fluids or subjected to some other acute osmotic or nonosmotic stimulus, these individuals invariably increase plasma AVP normally, but the resultant increase in urine concentration is usually subnormal because their renal capacity to concentrate the urine is also blunted by chronic polyuria. Thus, their antidiuretic response to these stimuli may be indistinguishable from that in patients with partial pituitary, partial gestational, or partial nephrogenic DI

Diferential Dx: When symptoms of urinary frequency, enuresis, nocturia, and/or persistent thirst are present, a 24-h urine should be collected on an ad libitum fluid intake. If the volume exceeds 50 mL/kg per day (3500 mL in a 70-kg man), polyuria is present. If the osmolarity is >300 mosmol/L, the polyuria is due to a solute diuresis and the patient should be evaluated for glucosuria or other less common causes of excessive solute excretion. However, if the 24-h urine osmolarity is <300> Except in the rare patient who is clearly dehydrated under basal conditions of ad libitum fluid intake, this evaluation should begin with a fluid deprivation test. If fluid deprivation does not result in urine concentration (osmolarity > 300 mosmol/L, specific gravity > 1.010) before body weight decreases by 5% or plasma osmolarity/sodium exceed the upper limit of normal, the patient has severe pituitary or severe nephrogenic DI. These disorders can usually be distinguished by administering desmopressin (DDAVP, 0.03 microg/kg SC or IV) and repeating the measurement of urine osmolarity 1–2 h later. An increase of >50% indicates severe pituitary DI, whereas a smaller or absent response is strongly suggestive of nephrogenic DI. If fluid deprivation results in concentration of the urine, the differential diagnosis is more difficult because the patient can have either partial pituitary DI, partial nephrogenic DI, or a form of primary polydipsia. In this situation, the change in urine osmolarity after the administration of desmopressin does not differentiate the possible disorders because the responses are variable and overlap in the three types of DI. The best way to differentiate between them is to measure plasma or urine AVP before and during the fluid deprivation test and analyze the results in relation to the concurrent plasma or urine osmolarity. This approach invariably differentiates partial nephrogenic DI from partial pituitary DI and primary polydipsia. It also differentiates partial pituitary DI from primary polydipsia if the hormone is measured when plasma osmolarity or sodium is clearly above the normal range. The requisite level of hypertonic dehydration may be difficult to produce by fluid deprivation alone when the urine is concentrated. Therefore, it is usually necessary to infuse hypertonic (3%) saline at a rate of 0.1 mL/kg per min while continuing the fluid deprivation and repeat the AVP measurements as soon as plasma osmolarity rises to >300 mosmol/L (Na⁺ > 145 mmol/L). This endpoint is usually reached within 30–120 min.

In most healthy adults and children, the posterior pituitary emits a hyperintense signal in T1-weighted mid-sagittal images. This "bright spot" is almost always present in patients with primary polydipsia but is invariably absent or abnormally small in patients with pituitary DI. Thus, a normal bright spot virtually excludes pituitary DI, is against nephrogenic DI, and strongly suggests primary polidipsia.

Treatment: It is also more resistant to degradation than AVP and has a three- to fourfold longer duration of action. Desmopressin (DDAVP) can be given by IV or SC injection, nasal inhalation, or oral tablet. The doses required to completely control pituitary DI vary widely, depending on the patient and the route of administration. However, they usually range from 1–2 microg qd or bid by injection, 10–20 microg bid or tid by nasal spray, or 100–400 microg bid or tid orally. The onset of action is rapid, ranging from as little as 15 min after injection to 60 min after oral administration.

Primary polydipsia cannot be treated safely with desmopressin. It inhibits the polyuria but, unlike pituitary DI, does not eliminate the urge to drink. Therefore, it almost always produces water intoxication within 24–48 h. Iatrogenic polydipsia can often be corrected by patient counseling, but there is no effective treatment for either psychogenic or dipsogenic DI. The symptoms and signs of nephrogenic DI are not affected by treatment with desmopressin but may be reduced by treatment with a thiazide diuretic and/or amiloride in conjunction with a low-sodium diet. Inhibitors of prostaglandin synthesis (e.g., indomethacin) are also very effective in some patients