Decreased secretion or action of AVP usually manifests as diabetes insipidus, a syndrome characterized by the production of abnormally large volumes of dilute urine. The 24-hour urine volume is >50 mL/kg body weight, and the osmolarity is <300 mosmol/L. The polyuria produces symptoms of urinary frequency, enuresis, and/or nocturia, which may disturb sleep and cause mild daytime fatigue or somnolence. It also results in a slight rise in plasma osmolarity that stimulates thirst and a commensurate increase in fluid intake (polydipsia). Overt clinical signs of dehydration are uncommon unless fluid intake is impaired.
ETIOLOGY
Deficient secretion of AVP can be primary or secondary.
The primary form usually results from agenesis or irreversible destruction of the neurohypophysis and is referred to variously as neurohypophyseal DI, pituitary DI, or central DI. It can be caused by a variety of congenital, acquired, or genetic disorders, but in about one-half of all adult patients it is idiopathic . The surgically induced forms of pituitary DI usually appear within 24 hours and then go through a 2- to 3-week interim period of inappropriate antidiuresis, after which they may or may not recur. The genetic form usually is 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. All the mutations alter one or more amino acids known to be critical for correct folding of the prohormone, thus interfering with its processing and trafficking through the endoplasmic reticulum. The AVP deficiency and DI develop gradually several months to years after birth, progressing from partial to severe and permanent DI. They appear to result from accumulation of misfolded mutant precursor followed by selective degeneration of AVP-producing magnocellular neurons. 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)] have also been described. A primary deficiency of plasma AVP also can result from increased metabolism by an N-terminal aminopeptidase produced by the placenta. It is referred to as gestational DI since the signs and symptoms manifest during pregnancy and usually remit several weeks after delivery.
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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, 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, and multiple sclerosis but is often idiopathic.
The second subtype, psychogenic polydipsia, is not associated with thirst, and the polydipsia seems to be a feature of psychosis or obsessive compulsive disorder.
The third subtype,iatrogenic polydipsia, results from recommendations to increase fluid intake for its presumed health benefits.
Primary deficiencies in the antidiuretic action of AVP result in nephrogenic DI. They can be genetic, acquired, or drug induced. The genetic form usually is transmitted in a semirecessive X-linked manner and is caused by mutations in the coding region of the V2receptor gene that impair trafficking and/or ligand binding of the mutant receptor. Autosomal recessive or dominant forms are caused by AQP2 gene mutations that result in complete or partial defects in trafficking and function of the water channels in distal and collecting tubules of the kidney.
Secondary deficiencies in the antidiuretic response to AVP result from polyuria per se. They are caused by washout of the medullary concentration gradient and/or suppression of aquaporin function. They usually resolve 24–48 hours after the polyuria is corrected but can complicate interpretation of some acute tests used for differential diagnosis.
PATHOPHYSIOLOGY
When the secretion or action of AVP falls below 80–85% of normal, urine concentration ceases and the rate of urine output rises to symptomatic levels. If the defect is due to pituitary, gestational, or nephrogenic DI, 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. As a result, hypernatremia and otherovert physical or laboratory signs of dehydration do not develop unless the patient also has a defect in thirstor fails to drink for some other reason.
The severity of the antidiuretic defect varies markedly from patient to patient. In some, the deficiencies in AVP secretion or action are so severe that even an intense stimulus such as nausea or severe dehydration does not raise plasma AVP enough to concentrate the urine. In others, the deficiency is incomplete, and a modest stimulus such as a few hours of fluid deprivation, smoking, or a vasovagal reaction increases plasma AVP sufficiently to raise urine osmolarity as high as 800 mosmol/L. The maximum achieved is usually less than normal, but that is the case largely because maximal concentrating capacity is temporarily impaired by chronic polyuria.
In primary polydipsia, the pathogenesis of the polydipsia and polyuria is the reverse of that in pituitary, nephrogenic, and gestational DI. Thus, the excessive intake of fluids slightly increases body water, thereby reducing plasma osmolarity, AVP secretion, and urinary concentration. The latter results in a compensatory increase in urinary free-water excretion that varies in direct proportion to intake. Therefore, hyponatremia or clinically appreciable overhydration is uncommon unless the polydipsia is very severe or the compensatory water diuresis is impaired by a drug or disease that stimulates or mimics endogenous AVP.
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 another acute osmotic or nonosmotic stimulus, these individuals invariably increase plasma AVP normally, but the resultant increase in urine concentration is usually subnormal because the individuals' renal capacities to concentrate the urine also are blunted temporarily by chronic polyuria. Thus, the maximum level of urine osmolarity achieved is usually indistinguishable from that in patients with partial pituitary, partial gestational, or partial nephrogenic DI. Patients with psychogenic or iatrogenic polydipsia respond similarly to fluid restriction but do not complain of thirst and usually offer other explanations for their high fluid intake.
DIFFERENTIAL DIAGNOSIS
When symptoms of urinary frequency, enuresis, nocturia, and/or persistent thirst are present, the possibility of DI should be evaluated after excluding glucosuria by collecting a 24-hour urine on ad libitum fluid intake. If the volume exceeds 50 mL/kg per day (3500 mL in a 70-kg male) and the osmolarity is >300 mosmol/L, DI is confirmed and the patient should be evaluated further to determine the type.
In differentiating among the various types of DI, the history alone may be sufficient if it reveals a likely antecedent such as pituitary surgery. Usually, however, that type of indicator is absent, ambiguous, or misleading and other approaches are needed. Except in the rare patient with hypertonic dehydration under basal conditions, differentiation should begin with a fluid deprivation test. It can be performed on an outpatient basis if the necessary staff and facilities are available. To minimize patient discomfort, avoid excessive dehydration, and maximize the information obtained, the test should be started in the morning and continued with hourly monitoring of body weight, plasma osmolarity and/or sodium concentration, urine volume, and urine osmolarity until either of two endpoints is reached. 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 rise above the upper limit of normal, the patient has severe pituitary or severe nephrogenic DI. These disorders usually can be distinguished by administering desmopressin (0.03 ug/kg SC or IV) and repeating the measurement of urine osmolarity 1–2 hours later. An increase of >50% indicates severe pituitary DI, whereas a smaller or absent response is strongly suggestive of nephrogenic DI.
Conversely, if fluid deprivation results in concentration of the urine, severe defects in AVP secretion and action are excluded and the question becomes whether the patient has partial pituitary DI, partial nephrogenic DI, or primary polydipsia. The maximum levels of urine osmolarity achieved before and after desmopressin injection are of no help in this regard because the values in the three groups vary widely and overlap owing to impairment of renal concentrating capacity caused by polyuria per se. Therefore, another approach is needed to differentiate among them. The easiest and least expensive method is to measure plasma AVP before and during the fluid deprivation test and analyze the results in relation to the concurrent plasma and urine osmolarity (Fig. 340-3). This approach invariably differentiates partial nephrogenic DI from partial pituitary DI and primary polydipsia. It also differentiates partial pituitary DI from primary polydipsia if plasma osmolarity and/or sodium are clearly above the normal range when the hormone is measured. However, the requisite level of hypertonic dehydration may be difficult to produce by fluid deprivation alone when urine concentration occurs. Therefore, it is usually necessary to continue the fluid deprivation and infuse hypertonic (3%) saline at a rate of 0.1 mL/kg per min until plasma osmolarity/sodium measured every 20 to 30 minutes reach or slightly exceed the upper limit of normal. At that point the plasma osmolarity/sodium, which is usually reached in 30 to 90 minutes, the measurement of plasma AVP should be repeated and the result related to plasma osmolarity/sodium is as before.
An alternative method of differential diagnosis is MRI of the pituitary and hypothalamus. In most healthy adults and children, the posterior pituitary emits a hyperintense signal in T1-weighted midsagittal 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. It is usually also small or absent in nephrogenic DI presumably because of high secretion and turnover of AVP. Thus, a normal bright spot virtually excludes pituitary DI, argues against nephrogenic DI, and strongly suggests primary polydipsia. Lack of the bright spot is less helpful, however, because it is absent not only in pituitary and nephrogenic DI but also in some healthy adults and patients with empty sella who do not have DI or AVP deficiency.
The other way to distinguish among the three basic types of DI is a closely monitored trial of desmopressin therapy.
TREATMENT: DIABETES INSIPIDUS
The signs and symptoms of uncomplicated pituitary DI can be eliminated completely by treatment with desmopressin (DDAVP), a synthetic analogue of AVP . DDAVP acts selectively at V2 receptors to increase urine concentration and decrease urine flow in a dose-dependent manner . It is also more resistant to degradation than is AVP and has a three- to fourfold longer duration of action. Desmopressin can be given by IV or SC injection, nasal inhalation, or oral tablet. The doses required to control pituitary DI completely vary widely, depending on the patient and the route of administration. However, they usually range from 1–2 ug qd or bid by injection, 10–20 ug bid or tid by nasal spray, or 100–400 ug bid or tid orally. The onset of action is rapid, ranging from as little as 15 minutes after injection to 60 minutes after oral administration. When given in doses sufficient to normalize urinary osmolarity and flow completely, desmopressin produces a slight (1–3%) increase in total body water and a commensurate decrease in plasma osmolarity and sodium concentration that rapidly eliminates thirst and polydipsia. Consequently, water balance is maintained and hyponatremia does not develop unless the osmoregulation of thirst is also impaired or fluid intake is excessive for another reason such as a misconception about the need to prevent dehydration. Fortunately, thirst abnormalities are rare in pituitary DI, and other motivations to drink excessively usually can be eliminated by patient education. Therefore, desmopressin usually can be given safely in doses sufficient to normalize urine output completely, thereby avoiding the inconvenience and discomfort of intermittent escape otherwise needed to prevent water intoxication.
Primary polydipsia cannot be treated safely with desmopressin or any other antidiuretic drug because eliminating the polyuria does not eliminate the urge to drink. Therefore, it produces hyponatremia and/or other signs of water intoxication, usually within 24 to 48 hours if urine output is normalized completely. Patient education may eliminate iatrogenic polydipsia, but it is largely ineffective in psychogenic or dipsogenic DI. In these patients, the only help currently available is to try to prevent water intoxication by warning about the use of drugs that can impair urinary free-water excretion directly or indirectly.
The polyuria and polydipsia of nephrogenic DI are not affected by treatment with standard doses of desmopressin. If resistance is partial, it may be overcome by tenfold higher doses, but this treatment is too expensive and inconvenient to be useful chronically. However, treatment with conventional doses of a thiazide diuretic and/or amiloride in conjunction with a low-sodium diet and a prostaglandin synthesis inhibitor (e.g., indomethacin) usually reduces the polyuria and polydipsia by 30–70% and may eliminate them completely in some patients. Side effects such as hypokalemia and gastric irritation can be minimized by the use of amiloride or potassium supplements and by taking medications with meals.
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