AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Central diabetes insipidus (DI) 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. The rare hereditary form of nephrogenic diabetes insipidus is transmitted as an X-linked genetic defect of the V2 receptor gene. A rare autosomal variant is caused by mutation in the aqua porin gene AQP2, a water-channel exclusively expressed in the collecting ducts of the kidney.

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.

Frequency

United States

Diabetes insipidus is uncommon, with a prevalence of 1 case per 25,000 people.

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 prevalence are equal.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.  
• • 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.
  • Second, an antidiuretic phase of 5-6 days occurs, which results from release of stored hormone. The urine osmolality rises.
  • 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.
• Patients with a nontraumatic onset typically have 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 ability to access water; those 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

Recent literature indicates 30% of cases to be idiopathic, 25% related to malignant or benign tumors of the brain or pituitary, 16% secondary to head trauma, and 20% following cranial surgery.

• Idiopathic diabetes insipidus 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 may show abnormalities of these structures. The presence of antibodies directed against vasopressin cells may help predict the development of central diabetes insipidus.
• Familial diabetes insipidus is rare. It is inherited as an autosomal dominant disorder, and mutations involving AVP-neurophysin gene have been identified. Mutations reported to date involve signal peptide region or, more commonly, neurophysin II. 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.
• Diabetes insipidus after neurosurgery or trauma varies with the extent of damage. Approximately 10-20% of patients will experience diabetes insipidus following transsphenoidal removal of an adenoma. This percentage increases to 60-80% with large tumors. Not all cases of diabetes insipidus are permanent. The most common causes of postoperative polyuria are excretion of excess fluid given during surgery and an osmotic diuresis as a result of treatment for cerebral edema.²
• Primary intracranial tumors causing diabetes insipidus 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 diabetes insipidus is necessary to detect slowly growing intracranial lesions.
• Other causes 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Psychogenic polydipsia
Osmotic diuresis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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.  
• • 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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 insipidus where the signal is still present.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 hyposmolar to the patient's serum. Avoid hyperglycemia, volume overload, and a correction of hypernatremia that is too rapid. A good rule of thumb is to reduce serum sodium by 0.5 mmol/L/h. 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.³ Generally, it can be administered 2-3 times per day. Patients may require hospitalization to establish fluid needs. Frequent electrolyte monitoring is recommended.
• Pharmaceutical therapy for diabetes insipidus includes subcutaneous, nasal, and oral preparations of vasopressin analogues, as well as chlorpropamide, carbamazepine, clofibrate (no longer on 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, 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treat diabetes insipidus (DI) with desmopressin and/or nonhormonal drugs. 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.

Drug Category: Hormones

These agents prevent complications of DI and reduce morbidity.

Drug Category: Hypoglycemics

These agents help relieve diuresis.

Drug Category: Anticonvulsants

Certain antiepileptic drugs, such as carbamazepine, have proven helpful in DI.

Drug Category: Antilipemic agents

Certain antiepileptic drugs, such as clofibrate, may increase the release of ADH in partial DI.

Drug Category: Diuretics

These agents may reduce flow to the ADH-sensitive distal nephron.

Drug Category: Nonsteroidal Anti-inflammatory Agents (NSAIDs)

Their mechanism of action is not known, but they may act by inhibiting prostaglandin synthesis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Earley LE, Orloff J. The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus. J Clin Invest. Nov 1962;41(11):1988-97.
2. Seckl J, Dunger D. Postoperative diabetes insipidus. BMJ. Jan 7 1989;298(6665):2-3. [Medline].
3. Richardson DW, Robinson AG. Desmopressin. Ann Intern Med. Aug 1985;ID - NIH5M01(2):228-39. [Medline].
4. Charmandari E, Brook CG. 20 years of experience in idiopathic central diabetes insipidus [letter]. Lancet. Jun 26 1999;353(9171):2212-3. [Medline].
5. Czernichow P, Robinson AG. Diabetes insipidus in man. Frontiers of Hormone Research. 1985;13-24.
6. Pivonello R, De Bellis A, Faggiano A, et al. Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology. J Clin Endocrinol Metab. Apr 2003;88(4):1629-36. [Medline].
7. Robertson GL. Diagnosis of diabetes insipidus. Frontiers of Hormone Research. 1985;13:176-89.
8. Rose BD. Clinical Physiology of Acid-Base and Electrolyte Disorders. 4th ed. New York, NY:. McGraw-Hill;1994:698-720.

Article Last Updated: Feb 13, 2008