REVIEW AMGAD N. MAKARYUS, MD SAMY I. McFARLANE, MD, MPH CME North Shore University Hospital, New York University State University of New York-Downstate and Kings CREDIT School of Medicine, Manhasset, NY County Hospital Center, Brooklyn, NY Diabetes insipidus: Diagnosis and treatment of a complex disease ■ ABSTRACT ATIENTS WHO PRESENT with diabetes P insipidus need immediate care because Diabetes insipidus, characterized by excretion of copious the body’s delicate water and electrolyte bal- volumes of dilute urine, can be life-threatening if not ance is threatened. It is essential to perform a properly diagnosed and managed. It can be caused by knowledgeable assessment based on character- two fundamentally different defects: inadequate or izing features, intervene rapidly with the prop- impaired secretion of antidiuretic hormone (ADH) from er treatment, and continue to reevaluate the the posterior pituitary gland (neurogenic or central patient’s condition. diabetes insipidus) or impaired or insufficient renal Complicating matters, the proper treat- response to ADH (nephrogenic diabetes insipidus). The ment depends on the cause in the individual distinction is essential for effective treatment. patient. Therefore, the physician must deter- mine whether the defect is in the brain or in ■ KEY POINTS the kidney. ■ Urine osmolality is easy to measure and helps in INABILITY TO CONSERVE WATER determining whether polyuria is due to diabetes insipidus or another condition. Diabetes insipidus is caused by the inability to conserve water and maintain an optimum free water level. The kidneys pass large The water deprivation test can help in distinguishing amounts of dilute urine regardless of the central diabetes insipidus from nephrogenic diabetes body’s hydration state, leading to symptoms of insipidus. extraordinary thirst, copious water intake (up to 20 liters per day), dry skin, and constipa- ADH preparations are used in treating central diabetes tion. insipidus but do not help in nephrogenic diabetes Two very different mechanisms can cause insipidus. diabetes insipidus (FIGURE 1): • Inadequate release of antidiuretic hor- Nephrogenic diabetes insipidus is treated by correcting mone (ADH, also called vasopressin) hypokalemia and hypercalcemia and by discontinuing any from the hypothalamus (central diabetes drugs that may be causing it. Thiazide diuretics are also insipidus) and • Inadequate response of the kidney to used. ADH (nephrogenic diabetes insipidus). The distinction is essential, since the treatment is different for the two causes, and is best achieved by a combination of hormonal and clinical observations.1–3 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006 65 DIABETES INSIPIDUS MAKARYUS AND McFARLANE T ABLE 1 osmolality is then measured 30 and 60 minutes later. Plasma osmolality is also measured at var- Causes of central ious points during the test. diabetes insipidus In normal subjects and patients with psy- Injury to the central nervous system chogenic diabetes insipidus (ie, due to mental Neoplastic/autoimmune disease disturbances that lead to excess fluid intake, Hypothalamic or pituitary surgery or ischemia which suppresses ADH secretion), the urine Radiation to the brain osmolality is greater than the plasma osmolal- Infection: meningitis, encephalitis ity following fluid restriction, and the urine Cerebral edema osmolality increases only minimally (< 10%) Intracranial hemorrhage after ADH injection. Familial disease In central diabetes insipidus, urine osmo- Idiopathic* lality remains less than plasma osmolality after dehydration. After ADH injection, urine *Some cases may be due to autoimmune or genetic osmolality increases by more than 50%. disorders or psychogenic polydipsia In nephrogenic diabetes insipidus, urine osmolality remains less than plasma osmolali- ty; after giving ADH, urine osmolality increas- es by less than 50%.2,3 ■ EVALUATING POLYURIA, DIAGNOSING DIABETES INSIPIDUS ■ CENTRAL DIABETES INSIPIDUS Polyuria is defined as urine volume of more Central diabetes insipidus results from any than 3 liters in 24 hours. The history is essen- condition that impairs the synthesis, trans- tial in differentiating diabetes insipidus from port, and release of ADH. It occurs in both other causes of polyuria and in determining sexes equally and affects all ages, with the the cause of diabetes insipidus. most frequent age of onset between 10 and 20 In central Urine osmolality is an easy differentiating years. diabetes test. A urine osmolality of 300 mOsmol/kg or The main evidence of ill health is polyuria more plus a high serum glucose level points to and polydipsia (besides the symptoms from the insipidus, thirst the diagnosis of diabetes mellitus; high urine underlying disease that damaged the neurohy- is so extreme osmolality plus high serum urea points to renal pophyseal system in the first place). Water disease. If the urine osmolality is less than 200 deprivation for even a short time results in it wakens the mOsmol/kg in the presence of polyuria, then rapid dehydration and compulsive thirst. The patient at night diabetes insipidus is present. A water depriva- thirst is so extreme that it even awakens the tion test, although not required for the diag- patient during the night. nosis of diabetes insipidus, is helpful in differ- The complete form of the disease is less entiating between central and nephrogenic common than a more moderate partial form diabetes insipidus. with only moderately excessive diuresis. As The water deprivation test, which should long as the thirst center remains intact and be done only by experienced physicians, the patient can seek water, the osmotic con- involves withholding all fluids until the patient centration of plasma usually remains around is sufficiently dehydrated to provide a potent values only slightly exceeding 290 mOsm/kg stimulus for ADH secretion. Deprivation lasts 4 (normal value 280–295 mOsm/kg).1 to 18 hours, with hourly measurements of body weight and urine osmolality, until two or three Causes of central diabetes insipidus consecutive samples vary by less than 30 The causes of central diabetes insipidus mOsm/kg (or < 10%) or until the patient loses (TABLE 1) can be divided into three major cat- 5% of his or her body weight. At this point, the egories. serum ADH level is measured, and then 5 units Damage to the hypothalamo-neurohy- of ADH or 1 µg of desmopressin (DDAVP, a pophyseal region due to head trauma, surgery, synthetic analogue of ADH) is injected. Urine or primary or metastatic tumors.1–3 66 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006 ■ Two different mechanisms of diabetes insipidus Diabetes insipidus, characterized by excretion of copious volumes of dilute urine, can be caused by a variety of defects that fall into two broad categories: central and nephrogenic. Central diabetes insipidus results from any condition (injury, genetic defect, or idiopathic cause) that impairs the synthesis, transport, or release of antidiuretic hormone (ADH; TABLE 1). ADH is normally produced in the hypothalamus and travels along nerve fibers to the posterior pituitary, where it is stored and released. Increased plasma osmolality normally Posterior stimulates release of ADH. If urine pituitary osmolality remains lower than plasma osmolality during fluid restriction, the patient may have central diabetes insipidus. ADH normally promotes reabsorption of water in the collecting duct of nephrons. If urine osmolality does not increase after injection of exogenous ADH, the patient may have nephrogenic diabetes inispidus. Nephrogenic diabetes insipidus results from inability of the kidneys to respond to ADH, owing to kidney disease, drug toxicity, or other causes H2O (TABLE 2). Collecting duct CCF Medical Illustrator: Beth Halasz ©2006 FIGURE 1 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006 67 DIABETES INSIPIDUS MAKARYUS AND McFARLANE Damage to the proximal part of this sensi- gliosis of variable numbers of supraoptic and tive region kills more neurons of the hypo- paraventricular nuclei, usually accompanied thalamo-neurohypophyseal tract than do dis- by a small posterior pituitary gland.4 tal injuries. Proximal lesions account for 30% to 40% of all cases of posttraumatic and post- Treatment of central diabetes insipidus operative diabetes insipidus, whereas distal Water is essential: in sufficient quantity, it lesions (below the median eminence) account will correct any metabolic abnormality due to for 50% to 60%. With the low (distal) lesions, excessive dilute urine. only a small proportion of magnocellular neu- ADH replacement. The earliest available rons degenerate, and intact cell bodies are preparation of ADH was a crude acetone dried able, over weeks to months, to regenerate new extract from bovine or porcine posterior pitu- axonal terminals at the level of the portal ves- itary, given by nasal insufflation. Problems sels of the median eminence.4 with this preparation included variable dura- Identification of the anatomical location tion of activity and local irritation of the nasal in the brain of the area of neuronal damage is mucosa. often helpful and necessary in the assessment Subsequently, a more purified preparation of the functional significance of the lesion. of ADH was developed, known as Pitressin This is performed with magnetic resonance (vasopressin tannate in oil). This is given intra- imaging of the hypothalamus and pituitary. muscularly every 2 to 4 days and provides relief Idiopathic