Introduction
Background
Diabetes insipidus (DI) may be central or nephrogenic. Central diabetes insipidus is characterized by decreased secretion of antidiuretic hormone (ADH), also known as arginine vasopressin (AVP), that results in polyuria and polydipsia by diminishing the patient's ability to concentrate urine. Diminished or absent ADH can be the result of a defect in one or more sites involving the hypothalamic osmoreceptors, supraoptic or paraventricular nuclei, or the supraopticohypophyseal tract. In contrast, lesions of the posterior pituitary rarely cause permanent diabetes insipidus because ADH is produced in the hypothalamus and still can be secreted into the circulation.
Nephrogenic diabetes insipidus is characterized by a decrease in the ability to concentrate urine due to a resistance to ADH action in the kidney.1 Nephrogenic diabetes insipidus can be observed in chronic renal insufficiency, lithium toxicity, hypercalcemia, hypokalemia, and tubulointerstitial disease; rarely, diabetes insipidus may be hereditary.
Recent studies
In a study of 89 patients with traumatic brain injury (TBI), Krahulik et al investigated the incidence of neuroendocrine dysfunction following TBI. The patients' hormonal function was evaluated at the time of injury, as well as afterward at 3, 6, and 12 months. The authors found primary hormonal dysfunction—including major deficits such as DI, growth hormone dysfunction, and hypogonadism — in 19 patients (21% of the cohort). The major deficits tended to occur in patients with the worst Glasgow Outcome Scale scores. Moreover, the occurrence of empty sella syndrome, as revealed on magnetic resonance imaging (MRI) scans, was highest in patients with deficits. The authors recommended that pituitary hormone testing be routinely performed within 6 months and 1 year postinjury in patients who have sustained a moderate to severe TBI.2
Pathophysiology
ADH is the primary determinant of free water excretion in the body. Its main target is the kidney, where it acts by altering the water permeability of the cortical and medullary collecting tubules. Water is reabsorbed by osmotic equilibration with the hypertonic interstitium and returned to the systemic circulation. The actions of ADH are mediated through at least 2 receptors: V1 mediates vasoconstriction, enhancement of corticotrophin release, and renal prostaglandin synthesis; V2 mediates the antidiuretic response.3,4
Frequency
United States
Diabetes insipidus is uncommon, with a prevalence of 1 case per 25,000 population.
Mortality/Morbidity
* Mortality is rare in adults as long as water is available.
* Severe dehydration, hypernatremia, fever, cardiovascular collapse, and death can ensue in children, elderly people, or in those with complicating illnesses.
Sex
* No significant sex differences in central or nephrogenic diabetes insipidus exist.
* Male and female prevalences are equal.
Clinical
History
The clinical presentation of diabetes insipidus (DI) depends on the cause, the severity, and the associated medical condition(s) of the patient.
* The most common form of diabetes insipidus is that which follows trauma or surgery to the region of the pituitary and hypothalamus. It may exhibit 1 of 3 patterns: transient, permanent, or triphasic. The triphasic pattern is observed more often clinically.
o First, a polyuric phase occurs and lasts 4-5 days. Inhibition of ADH causes the polyuric phase. An immediate increase in urine volume and a concomitant fall in urine osmolality occur.
o Second, an antidiuretic phase of 5-6 days occurs, which results from release of stored hormone. The urine osmolality rises.
o The third phase can be permanent diabetes insipidus, when stores of ADH are exhausted and the cells that produce more ADH are absent or unable to produce.
* Polyuria, polydipsia, and nocturia (from 3-18 L) are the predominant symptoms.
* In infants, crying, irritability, growth retardation, hyperthermia, and weight loss may be the most apparent signs.
* In children, enuresis, anorexia, linear growth defects, and fatigability typically predominate.
* When it has a nontraumatic cause, diabetes insipidus typically has a much more indolent course.
* Pregnancy is associated with an increased risk of diabetes insipidus.
* Polyuria, polydipsia, hydronephrosis, bladder enlargement, and signs of dehydration are common.
* Symptoms and signs of simultaneous anterior pituitary dysfunction may be present but are rare.
* The daily urine volume is highly variable (3-20 L/d), and patient tolerance of dehydration also varies among individuals.
* Many patients have a predilection for drinking cold liquids, often water.
* Neurologic symptoms vary with the patient's access to water; patients with free access may have no symptoms at all.
Physical
The physical examination varies with the severity and chronicity of the diabetes insipidus.
* The examination findings may be entirely normal.
* Signs of dehydration and an enlarged bladder may be present; otherwise, no specific signs of diabetes insipidus exist.
Causes
The literature indicates that 30% of diabetes insipidus (DI) cases are idiopathic, 25% are related to malignant or benign tumors of the brain or pituitary, 16% are secondary to head trauma, and 20% follow cranial surgery.
* Idiopathic DI is associated with destruction of cells in the hypothalamus, often as part of an autoimmune process. This is characterized by lymphocytic infiltration of the stalk and posterior pituitary. An MRI scan may show abnormalities in these structures. The presence of antibodies directed against vasopressin cells may help to predict the development of central DI.
* The frequency with which DI develops after neurosurgery varies with the surgery's scope. Approximately 10-20% of patients experience DI following transsphenoidal removal of an adenoma, but the percentage of patients experiencing the condition postoperatively increases to 60-80% with large tumors. However, not all cases of DI are permanent. In a German study of metabolic disturbances after transsphenoidal pituitary adenoma surgery, only 8.7% of DI cases persisted for more than 3 months.5
* 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.6
* A prospective study in 436 patients who sustained severe head injury found that DI occurred in 15.4% of all such individuals.7
* Primary intracranial tumors causing DI include craniopharyngioma or pineal tumors. Appearance of other hypothalamic manifestations may be delayed for as long as 10 years. Thus, periodic follow-up of patients diagnosed with idiopathic DI is necessary to detect slowly growing intracranial lesions.
* Familial DI is rare. Almost 90% of hereditary cases of nephrogenic DI result from an X-linked defect of the AVP receptor 2 gene (AVPR2).8 A rare autosomal dominant variant results from the mutation of AQP2, an aquaporin gene that gives rise to a water channel that is expressed exclusively in the kidney's collecting ducts. Autosomal dominant central DI that involves mutations of the AVP - neurophysin gene has also been identified. Mutations reported to date involve the signal peptide region or, more commonly, neurophysin II.9 The mechanism by which the mutations impair AVP release is not understood but may involve the accumulation of the ADH precursor, leading to the death of the ADH-producing cells.
* Other causes of DI include cancer (eg, lung cancer, lymphoma, leukemia), hypoxic encephalopathy, infiltrative disorders (histiocytosis X, sarcoidosis), anorexia nervosa, and vascular lesions, such as arteriovenous malformations or aneurysms.Differential Diagnoses
Diabetes Mellitus, Type 1
Other Problems to Be Considered
Psychogenic polydipsia
Osmotic diuresis
Workup
Laboratory Studies
* The diagnosis of diabetes insipidus (DI) is often made clinically, while the laboratory tests provide confirmation. Perform testing with the patient maximally dehydrated as tolerated, that is, at a time when ADH release would be highest and urine would be most concentrated. Ruling out secondary causes, such as diabetes mellitus, is also important.
* The clinician should measure serum electrolytes and glucose, urine specific gravity, urinary sodium, simultaneous serum and urine osmolality, and ADH levels. A urine specific gravity of 1.005 or less and a urine osmolality less than 200 mOsm/kg is the hallmark of diabetes insipidus. Random plasma osmolality generally is greater than 287 mOsm/kg.
* The water deprivation test (ie, Miller-Moses test), a semiquantitative test to ensure adequate dehydration and maximal stimulation of ADH for diagnosis, is performed in ambiguous clinical circumstances, typically with more chronic forms of diabetes insipidus.
o The extent of deprivation is usually limited by the patient's thirst or by any significant drop in blood pressure or related clinical manifestation of dehydration.
o With mild polyuria, water deprivation can begin the night before the test. With severe polyuria, water restriction is carried out during the day to allow close observation.
o All water intake is withheld and urine osmolality and body weight are measured hourly. When 2 sequential urine osmolalities vary by less than 30 mOsm or if the weight decreases by more than 3%, 5 U of aqueous vasopressin is administered subcutaneously. A final urine specimen is obtained 60 minutes later for osmolality measurement.
o In healthy individuals, water deprivation leads to a urine osmolality that is 2-4 times greater than plasma osmolality. Administration of vasopressin results in less than 9% increment in urine osmolality. The time required to achieve maximal urine concentration ranges from 4-18 hours.
o In complete central diabetes insipidus, testing reveals minimal ADH levels and activity, with failure of the urine to be concentrated despite excessively concentrated serum. In response to exogenous vasopressin, urine osmolality increases by more than 50%.
o Patients with nephrogenic diabetes insipidus have a normal to elevated serum ADH level and failure of the kidney to respond to exogenous ADH during the water deprivation test.
Imaging Studies
* Brain MRI
* Pituitary MRI - T1-weighted images of the healthy posterior pituitary yield a hyperintense signal. In patients with central diabetes insipidus, this signal is absent, except in the rare familial form of central diabetes insipidusTreatment
Medical Care
* In an emergency, most patients with diabetes insipidus (DI) can drink enough fluid to replace their urine losses. Replace losses with dextrose and water or IV fluid hypo-osmolar to the patient's serum. Avoid hyperglycemia, volume overload, and overly rapid correction of hypernatremia. A good rule of thumb is to reduce serum sodium by 0.5 mmol/L/h. The water deficit may be calculated based on the assumption that body water is approximately 60% of body weight in kilograms.
* In case of inadequate thirst, desmopressin is the drug of choice.11,12 A synthetic analogue of AVP, desmopressin is available in subcutaneous, intranasal, and oral preparations.13 Generally, it can be administered 2-3 times per day. Patients may require hospitalization to establish fluid needs. Frequent electrolyte monitoring is recommended.
* Alternatives to desmopressin for pharmaceutical therapy for diabetes insipidus include synthetic vasopressin, as well as the nonhormonal agents chlorpropamide, carbamazepine, clofibrate (no longer on the US market), thiazides, and indomethacin (limited efficacy).
Surgical Care
* Postoperatively, administer the usual dose of desmopressin to patients with diabetes insipidus and administer (hypotonic) IV fluids to match urine output.
* After pituitary surgery, patients should undergo continuous monitoring of fluid intake, urine output, and specific gravities, along with daily measurements of serum electrolytes.14 In patients who develop diabetes insipidus, administer parenteral desmopressin every 12-24 hours, along with adequate fluid to match losses. Follow the specific gravity of the urine and administer the next dose of desmopressin when the specific gravity has fallen to less than 1.008-1.005 with an increase in urine output. When the patient can tolerate oral intake, thirst can become an adequate guide.
Consultations
In the setting of neurosurgery or head trauma, the diagnosis of diabetes insipidus may be obvious and even expected. The intensivists and the nurses who manage the patient acutely are in the best position to treat acutely. In the more subtle forms, and certainly in all chronic forms in which therapy is anticipated to be indefinite, the clinical endocrinologist is invaluable to establish the diagnosis and to design therapy.
Diet
* No specific dietary considerations exist in chronic diabetes insipidus, but the patient should understand the importance of adequate and balanced salt and water intake.
* Patients with diabetes insipidus also must take special precautions, such as when traveling, to be prepared to treat vomiting or diarrhea and to avoid dehydration with exertion or hot weather.
Medication
Treat diabetes insipidus (DI) with desmopressin and/or nonhormonal drugs.12 In central diabetes insipidus, the primary problem is a hormone deficiency; therefore, physiologic replacement with desmopressin is usually effective. Use a nonhormonal drug if response is incomplete or desmopressin is too expensive. Nonhormonal drugs usually are more effective in treating nephrogenic diabetes insipidus.
Hormones
These agents prevent complications of DI and reduce morbidity.
Desmopressin (DDAVP)
Synthetic analogue of arginine vasopressin with potent antidiuretic, but no vasopressor, activity.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
5-20 mcg intranasal qd/bid
0.05-0.8 mg PO once or more daily
Pediatric
0.05-0.3 mg/d PO
* Dosing
* Interactions
* Contraindications
* Precautions
Lithium and demeclocycline diminish ADH effects; chlorpropamide, fludrocortisone, and glucocorticoids enhance ADH response; monitor with pressor agents
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Observe for effects on blood pressure; institute fluid restriction in children to avoid hyponatremia or water intoxication
Vasopressin (Pitressin)
Has vasopressor and antidiuretic hormone (ADH) activity. Increases water resorption at collecting ducts (ADH effect) and promotes smooth muscle contraction throughout vascular bed of renal tubular epithelium (vasopressor effects). However, vasoconstriction is also increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels.
Decreases portal pressure in portal hypertension. A notable undesirable effect is coronary artery constriction that may dispose patients with coronary artery disease to cardiac ischemia. This can be prevented with concurrent use of nitrates.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
5-10 U SC q3-6h
Pediatric
2.5-10 U SC bid/qid
* Dosing
* Interactions
* Contraindications
* Precautions
Lithium, demeclocycline, and alcohol diminish ADH effects; chlorpropamide and fludrocortisone or glucocorticoids enhance ADH effects
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; coronary artery disease; hypertension; angina
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in cardiovascular disease, seizure disorders, nitrogen retention, asthma, or migraine; excessive doses may result in hyponatremia
Hypoglycemics
These agents help relieve diuresis.
Chlorpropamide (Diabinese)
Promotes renal response to ADH.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
125-250 mg PO bid
Pediatric
Not recommended
* Dosing
* Interactions
* Contraindications
* Precautions
NSAIDS, salicylates, sulfonamides, warfarin, monoamine oxidase inhibitors (MAOIs), and beta blockers may enhance hypoglycemia
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; type I diabetes; severe renal or hepatic impairment; thyroid dysfunction
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hypoglycemia may occur
Anticonvulsants
Certain antiepileptic drugs, such as carbamazepine, have proven helpful in DI.
Carbamazepine (Tegretol)
Amelioration by releasing ADH. Not useful in total DI and generally not a first-line drug.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
100-300 mg PO bid
Pediatric
Not recommended
* Dosing
* Interactions
* Contraindications
* Precautions
Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; carbamazepine may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels)
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; history of bone marrow suppression; MAOI use
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Do not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBCs and serum iron baseline prior to treatment, during first 2 months, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness
Antilipemic agents
Certain antilipemic drugs, such as clofibrate, may increase the release of ADH in partial DI.
Clofibrate (Atromid-S)
No longer on US market. May release ADH in partial DI.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
500 mg PO bid
Pediatric
Not recommended
* Dosing
* Interactions
* Contraindications
* Precautions
Rifampin decreases serum level and effect; anticoagulant effect of warfarin may be potentiated, with a greater increase in prothrombin time (PT); chlorpropamide may increase hypoglycemia; probenecid increases serum level and effect
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; hepatic or renal insufficiency; biliary cirrhosis
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Consider tumorigenicity; caution in breastfeeding, cardiac disease, and hypothyroidism
Diuretics
These agents may reduce flow to the ADH-sensitive distal nephron.
Hydrochlorothiazide (Esidrix, HydroDIURIL, Microzide)
Thiazide diuretic that decreases urinary volume in absence of ADH. May induce mild volume depletion and cause proximal salt and water retention, thereby reducing flow to the ADH-sensitive distal nephron. Effects are additive to other agents.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
25-50 mg PO qd or divided bid
Pediatric
Not recommended
* Dosing
* Interactions
* Contraindications
* Precautions
Alcohol, antihypertensive drugs, and other diuretics increase diuretic effect; corticosteroids and other diuretics increase hypokalemic effect; decreases hypoglycemic effect of insulin and oral agents; increases lithium serum levels; NSAIDs decrease diuretic and antihypertensive effects
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; renal dysfunction
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Considered pregnancy risk category D by some experts; observe for changes in fluids and electrolytes
Nonsteroidal Anti-inflammatory Agents (NSAIDs)
Their mechanism of action is not known, but they may act by inhibiting prostaglandin synthesis.
Ibuprofen (Ibuprin, Advil, Motrin)
Inhibition of prostaglandin synthesis reduces delivery of solute to distal tubules, reducing urine volume and increasing urine osmolality. Usually used in nephrogenic DI.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
600-800 mg PO tid
Pediatric
Not recommended
* Dosing
* Interactions
* Contraindications
* Precautions
Aspirin decreases serum levels; antiplatelet effect of low-dose aspirin can be compromised; increases serum levels of digoxin, methotrexate, lithium; increases effect of anticoagulants; decreases hypotensive effects of ACE inhibitors and furosemide
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; advanced renal disease; GI bleeding or risk of bleeding
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Pregnancy category D in third trimester; fluid retention, platelet effects, and renal disease may occur
Indomethacin (Indocin)
Inhibition of prostaglandin synthesis reduces delivery of solute to distal tubules, reducing urine volume and increasing urine osmolality. Usually used in nephrogenic DI.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
25-50 mg PO bid/tid
75 mg SR PO bid; not to exceed 200 mg/d
Pediatric
Not established
Follow-up
Further Inpatient Care
* Monitor for fluid retention and hyponatremia during initial therapy. Follow volume of water intake and frequency and volume of urination and inquire about thirst.
* Monitor serum sodium, 24-hour urine volumes, and specific gravity.
* Request posthospitalization follow-up visits with the patient every 6-12 months.
* Patients with normal thirst mechanisms can usually self-regulate.
Prognosis
Prognosis is excellent, depending upon underlying illness.
Patient Education
Patients must be instructed in simple principles of water balance to avoid dehydration and water intoxication (if not carefully monitoring water intake).
Miscellaneous
Medicolegal Pitfalls
The major issues are those of clarifying the diagnosis and etiology of diabetes insipidus, establishing appropriate therapy, and, most importantly, following up on a regular basis to monitor therapy.
