eMedicine Specialties > Endocrinology > Pituitary Gland

Diabetes Insipidus

Author: Michael Cooperman, MD, Clinical Associate Professor of Endocrinology, Temple University; Chair, Department of Internal Medicine, Division of Endocrinology, Jeanes Hospital
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Updated: Sep 25, 2009

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.

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 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. 
  • 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.
• 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. A magnetic resonance imaging (MRI) scan may show abnormalities of 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.²
• 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.³
• A prospective study in 436 patients who sustained severe head injury found that DI occurred in 15.4% of all such individuals.⁴
• 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).⁵ 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.⁶ 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.

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