DIABETES INSIPIDUS Diabetes insipidus (DI) is defined as the passage of large volumes (>3 L/24 hr) of dilute urine (< 300 mOsm/kg).

It has the following 2 major forms:
 

Central (neurogenic, pituitary, or neurohypophyseal) DI, characterized by decreased secretion of antidiuretic hormone (ADH; also referred to as arginine vasopressin [AVP]) Nephrogenic DI, characterized by decreased ability to concentrate urine because of resistance to ADH action in the kidney[1]

Two other forms are gestational DI and primary polydipsia (dipsogenic DI); both are caused by deficiencies in AVP, but the deficiencies do not result from a defect in the neurohypophysis or kidneys.

Essential update: Predicting permanent diabetes insipidus in children with craniopharyngioma
A retrospective analysis of 102 consecutive operations for craniopharyngioma (45 in children and 57 in adults) was carried out with the aim of determining the incidence, predictors, and early postoperative course of DI in this setting.[2] Postoperative DI was more common in children than in adults (80% vs 63%). Children also had a significantly higher incidence of permanent DI (55.6%), and radical excision was found to be a predictor of this result in pediatric patients (though not in adult patients, for whom previous tumor surgery and new-onset hypopituitarism were stronger predictors of permanent DI). The triphasic response, wide intraday serum sodium fluctuations, and hyponatremia were all more common in children as well. These findings suggest that postoperative DI may be more difficult to manage in pediatric patients and that additional alertness is required to detect the triphasic response in this group.[2]

Signs and symptoms
The predominant manifestations of DI are as follows:
  

Polyuria: The daily urine volume is relatively constant for each patient but is highly variable between patients (3-20 L) Polydipsia Nocturia

The most common form is central DI after trauma or surgery to the region of the pituitary and hypothalamus, which may exhibit 1 of the following 3 patterns:
  

Transient Permanent Triphasic (observed more often clinically)

In infants with DI, the most apparent signs may be the following:

Diagnosis If the clinical presentation suggests DI. or pain radiating to the testicle or genital area Bladder enlargement in some patients Dehydration if the thirst mechanism is impaired or access to fluid is restricted See Clinical Presentation for more detail. with pelvic fullness. the following manifestations typically predominate:     Enuresis Anorexia Linear growth defects Fatigability If the condition that caused DI also damaged the anterior pituitary or hypothalamic centers that produce releasing factors.     Crying Irritability Growth retardation Hyperthermia Weight loss In children. laboratory tests must be performed to confirm the diagnosis. patients may present with the following:      Excessive fatigue Diminished libido or erectile dysfunction Headache Dry skin Hair loss Physical findings vary with the severity and chronicity of DI. as follows:      A 24-hour urine collection for determination of urine volume Serum electrolyte concentrations and glucose level Urinary specific gravity Simultaneous plasma and urinary osmolality Plasma ADH level Additional studies that may be indicated include the following: . flank pain or tenderness. they may be entirely normal or may include the following:    Hydronephrosis.

) Nephrogenic DI is characterized by a decrease in the ability to concentrate urine because of resistance to ADH action in the kidney. and Workup. (See Etiology.) . Central DI is characterized by decreased secretion of antidiuretic hormone (ADH)—also known as arginine vasopressin (AVP)—which gives rise to polyuria and polydipsia by diminishing the person’s ability to concentrate urine. but only when no better options exist) See Treatment and Medication for more detail.  Water deprivation (Miller-Moses) test to ensure adequate dehydration and maximal stimulation of ADH for diagnosis Pituitary studies. hypokalemia. and Workup. hypercalcemia. Management Most patients with DI can drink enough fluid to replace their urine losses.[1] Nephrogenic DI can be observed in chronic renal insufficiency. including magnetic resonance imaging (MRI) and measurement of circulating pituitary hormones other than ADH See Workup for more detail. glucosuria. 4] ) Synthetic vasopressin Chlorpropamide Carbamazepine (rarely used. lithium toxicity. do not administer sterile water without dextrose IV Administer fluids at a rate no greater than 500-750 mL/hr. Presentation.5 mmol/L (0. and tubulointerstitial disease. When oral intake is inadequate and hypernatremia is present. aim at reducing serum sodium by approximately 0. employed only when all other measures prove unsatisfactory) Clofibrate (no longer on the US market) Thiazides Nonsteroidal anti-inflammatory drugs (NSAIDs). such as indomethacin (may be used in nephrogenic DI. (See Etiology. provide fluid replacement as follows:   Give dextrose and water or an intravenous fluid that is hypo-osmolar with respect to the patient’s serum.5 mEq/L) every hour Pharmacologic therapeutic options include the following:        Desmopressin (drug of choice for central DI[3. pituitary. and neurohypophyseal DI. Background Diabetes insipidus (DI) is defined as the passage of large volumes (>3 L/24 h) of dilute urine (< 300m Osm/kg). DI has 2 major forms: central and nephrogenic. Presentation. Other terms for central DI are neurogenic.

AVP. often before the age of 1 week. see Pediatric Diabetes Insipidus. In the brain. to excrete 1000 mOsm of solute.Mediates the antidiuretic response . In addition. enhancement of corticotrophin release. Rarely. 6] :   V1 .) Physiology of water balance The normal range of plasma osmolality is between 275 and 295 mOsm/kg. Primary polydipsia (dipsogenic DI) results from a primary defect in osmoregulation of thirst. This urine is maximally concentrated and appears dark yellow or orange in color. interrelated determinants: thirst. Conversely the maximum volume of urine (secondary to limits imposed by renal dilutional capacity) is 20 L of water per day (1000 mOsm per 50 mOsm/kg water). Its main target is the kidney.Mediates vasoconstriction. Gestational DI results from degradation of vasopressin by a placental vasopressinase. and renal prostaglandin synthesis V2 . AVP is the primary determinant of free water excretion in the body. Apelin acts as a potent diuretic neuropeptide that inhibits ADH release. as dipsogenic DI has been reported in tuberculous meningitis.Two other forms of DI are gestational DI and primary polydipsia. The ability of the kidneys to modify the concentration of urinary solutes ranges between 50–1200 mOsm/kg. but structural lesions may exist. the obligate urinary water excretion would be 1000 mOsm per 1200 mOsm/kg water. The maintenance of water balance in healthy humans is principally accomplished through 3 robust.[3] Hereditary nephrogenic DI manifests in early infancy. Thus. as well as in other sites. Pharmacologic treatment of DI generally involves the use of desmopressin (1-deamino-8-Darginine vasopressin [DDAVP]). and the kidneys. and neurosarcoidosis. This maximally dilute urine is colorless. Hereditary central DI typically manifests in childhood. it is expressed in supraoptic and paraventricular nuclei. which translates into 0.8 L) of water per day. The actions of AVP are mediated through at least 2 receptors. Apelin is a bioactive peptide that is widely distributed throughout the body. Both are caused by deficiencies in AVP. If this requirement for obligate water excretion is not met. and has specific receptors located on vasopressinergic neurons. where it acts by altering the water permeability of the cortical and medullary collecting tubules. recognition of a fourth factor. multiple sclerosis. DI may be hereditary. solutes accumulate. nonhormonal drugs. Healthy adults on a normal diet excrete 800–1200 mOsm of solute daily. apelin. Water is reabsorbed by osmotic equilibration with the hypertonic interstitium and returned to the systemic circulation. Patients must be instructed in simple principles of water balance to avoid dehydration and water intoxication (if they are not carefully monitoring water intake). but the deficiencies do not result from a defect in the neurohypophysis or kidneys. For more information on DI in children. The exact location of the lesion is not known. or both. as follows[5. has emerged in recent years. leading to uremia.8 kg (0. (See Treatment.

Diminished or absent ADH production can be the result of a defect in 1 or more sites in the neurohypophysis. the increased thirst in uncontrolled diabetes mellitus is secondary to volume depletion from osmotic diuresis.To preserve sodium retention Thirst .To raise water intake AVP secretion .Effects of reduced AVP or ADH The vasoconstrictor effect of AVP is negligible in humans. Response to volume decrease Ordinarily. In rare cases. Etiology DI is usually an acquired disorder.30% Malignant or benign tumors of the brain or pituitary .To increase water retention Volume depletion activates baroreceptor mechanisms that exert similar effects on aldosterone. a decrease in the extracellular fluid (ECF) volume elicits the following simultaneous responses:    Aldosterone secretion . and the supraopticohypophyseal tract. the supraoptic or paraventricular nuclei.25% Cranial surgery . Central diabetes insipidus Central DI has many possible causes. rather. responding preferentially to increased sodium levels in the ECF. and AVP. elevated glucose levels in diabetes mellitus do not induce thirst. with central DI having different causes than does nephrogenic DI. These include the hypothalamic osmoreceptors. According to the literature. Osmoreceptors for thirst are solute specific. the principal causes of central DI and their oft-cited approximate frequencies are as follows:     Idiopathic . central or nephrogenic DI may be an inherited disorder.20% Head trauma . thirst.16%[7] Idiopathic DI . Thus. whereas osmoreceptor-mediated mechanisms impact thirst and AVP secretion only. No clinically significant defects in blood pressure regulation or cortisol secretion are apparent in patients with DI.

Serial contrast-enhanced brain MRIs (every 3-6 months for the first 2 years) in patients with central DI who have pituitary stalk thickening may shorten the time to diagnosis of germinoma by as much as 1 year. Postoperative DI The frequency with which DI develops after neurosurgery varies with the surgery’s scope. In a German study of metabolic disturbances after transsphenoidal pituitary adenoma surgery. Approximately 10-20% of patients experience DI after transsphenoidal removal of an adenoma. and pineal tumors.[8] . Tumor-associated DI Primary intracranial tumors causing DI include craniopharyngiomas. germinomas.7% of DI cases persisted for more than 3 months. This disorder is characterized by lymphocytic infiltration of the stalk and posterior pituitary.Idiopathic central DI presumably develops when cells in the hypothalamus are damaged or destroyed. A negative result for hCG in the cerebrospinal fluid (CSF) does not exclude germinoma. Antibodies directed against vasopressin cells have been found in patients with idiopathic central DI. Surgery is the preferred treatment. only 8. Magnetic resonance imaging (MRI) may show abnormalities in these structures. compared with 60-80% of those who have undergone excision of large tumors. Increasingly. however. accounting for nearly 54% of cases. Identification of antibodies against AVP-secreting cells and advances in imaging techniques have made idiopathic cases less common than they previously were. close clinical and MRI follow-up is necessary. the role of inflammation and autoimmunity in DI is being recognized. Central DI insipidus and multiple pituitary hormone deficiencies are common manifestations in childhood craniopharyngiomas. The appearance of other hypothalamic manifestations may be delayed for as long as 10 years in these cases. among others. Cases of lymphocytic hypophysitis were possibly classified as idiopathic prior to improved imaging studies. which indicates that this finding can not be considered a reliable marker of autoimmune etiology in central DI. The role of human chorionic gonadotropin (hCG) in the early diagnosis of germinoma is not fully established. these antibodies have also been found in patients with Langerhans cell histiocytosis (LCH) or germinomas. Given the possible diagnostic confusion. It is the most frequent pediatric intracranial neoplasm. reliance on AVP antibodies may delay the diagnosis of LCH or germinoma. Indeed. Not all cases of postoperative DI are permanent. Craniopharyngioma is a benign tumor that arises from squamous cell nests in the primitive Rathke pouch.

which result from defects in the AVP-NP2 (AVP neurophysin) gene.[9] DI in head trauma Central DI can be an acute or chronic complication of head injury or subarachnoid hemorrhage. less commonly. leukemia Hypoxic encephalopathy Granulomatous disease . Diabetes Mellitus. as well as in the WFS1 gene. histiocytosis X. The defect results in the production of mutant prohormone that is toxic to the neuron and eventually destroys it.Eg. tuberculosis.[7. sickle cell disease.[13. metastatic lung cancer. a tetrameric protein that may serve as a novel endoplasmic reticular calcium channel in pancreatic beta cells and neurons. Sheehan syndrome. 10] Risk factors for acute DI include penetrating trauma and severe head trauma. The latter gene encodes for wolframin.[11] Hereditary central DI Approximately 10% of central DI cases are familial (although some experts suggest that familial DI may be underdiagnosed). aortocoronary bypass Nephrogenic diabetes insipidus . Additional causes Other causes of central DI include the following:      Cancer . Deafness). lymphoma. Optic Atrophy. 15] There are also autosomal recessive forms of DI. an X-linked form of neurohypophyseal DI exists.Eg. In addition. The most common causes of postoperative polyuria are excretion of excess fluid administered during surgery and an osmotic diuresis resulting from treatment for cerebral edema. adrenocorticotropic hormone deficiency) may accompany posttraumatic DI. aneurysms. sarcoidosis.Eg.[12] Most of these cases show autosomal dominant inheritance and result from a defect in the AVP-NP2 gene on chromosome 20p13. Mutations in WFS1 lead to Wolfram syndrome. Wegener granulomatosis Anorexia nervosa Vascular lesions . A specific genetic defect has not been identified.[7] Other forms of pituitary dysfunction (eg. may develop gradually.Postoperative polyuria does not necessarily indicate DI.[10] The dysfunction may be transient or. 14. arteriovenous malformations.[3] Genetic testing to determine the specific etiology can obviate the search for another cause.[3] Finding a genetic anomaly will also answer recurrence risk questions for the family. and may prove to be helpful with treatment options. which is also known by the acronym DIDMOAD (Diabetes Insipidus.[16] Another recessive form of central DI results from the production of biologically inactive AVP.

a gene on chromosome 12q13 that gives rise to a water channel that is expressed exclusively in the kidney’s collecting ducts. . amyloidosis Pregnancy (transient) Hyperglycemia (osmotic diuresis) In addition to lithium.Eg. Similarly. however. with a prevalence of 3 cases per 100. nephrogenic DI most often develops as a result of lithium toxicity or hypercalcemia. most cases occur in males. from sickle cell disease. Autosomal recessive and autosomal dominant forms of nephrogenic DI from AQP2 mutations have been reported.[21] No significant sex-related differences in central or nephrogenic DI exist.[17.[20] Approximately 1% of familial nephrogenic DI cases result from mutations in AQP2 (aquaporin 2). Because hereditary nephrogenic DI is an X-linked disorder. other drugs that can reduce urinary concentrating ability include the following:        Amphotericin B Cidofovir Demeclocycline Didanosine Foscarnet Ofloxacin Orlistat Hereditary nephrogenic DI Hereditary nephrogenic DI is relatively rare.75 mmol/dL can also impair urinary concentrating ability. Other causes of acquired nephrogenic DI include the following:     Hypokalemia Renal disease . Impairment of urinary concentration occurs in up to 20% of patients taking lithium.[19] Defects in the AVP receptor cause resistance to the antidiuretic effect of vasopressin.In adults.[4] The most common inherited form results from mutations in the AVP receptor 2 gene (AVPR2) on chromosome Xq28.000 population. with male and female prevalence being equal. as a result of dysregulation of the aquaporin system in principal cells of the collecting duct. 18] Prolonged elevation of serum calcium concentrations above 11 mg/dL (2.[3] Epidemiology DI is uncommon in the United States. cases occasionally arise in females as a result of skewed X inactivation. no significant differences in prevalence among ethnic groups have been found.

inherited causes account for approximately 1-2% of all cases. after many years of lithium use. depending on the underlying illness. fever. permanent nephrogenic DI may occur. and death can ensue in children and elderly people.[22] Prognosis The prognosis for patients with DI is generally excellent. lithium).With both central and nephrogenic DI. stopping the medication may help to restore normal renal function. cardiovascular collapse. however. as well as in persons with complicating illnesses. hypernatremia. An incidence of about 1 in 20 million births for nephrogenic DI caused by AQP2 mutations has been cited. . DI-related mortality is rare in adults as long as water is available. Severe dehydration. In nephrogenic DI caused by medication (eg.