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Harrison’s Manual of Medicine



Diabetes Insipidus
Syndrome of Inappropriate Antidiuretic Hormone (SIADH)
The neurohypophysis, or posterior pituitary gland, is formed by axons that project from the supraoptic and paraventricular nuclei of the hypothalamus. The posterior pituitary gland produces two hormones: (1) arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), and (2) oxytocin. AVP acts on the renal tubules to induce water retention, leading to concentration of the urine. Oxytocin stimulates postpartum milk letdown in response to suckling. Clinical syndromes may result from deficiency or excess of AVP. There are no known clinical disorders associated with oxytocin deficiency or excess.
Etiology   Diabetes insipidus (DI) results from abnormalities of AVP production from the hypothalamus or action in the kidney (Table 170-1). AVP deficiency is characterized by production of large amounts of dilute urine. In central DI, insufficient AVP is released in response to physiologic stimuli. Causes include congenital, acquired, or genetic disorders, but almost half the time it is idiopathic. In gestational DI, increased metabolism of plasma AVP by an aminopeptidase produced by the placenta leads to a deficiency of AVP during pregnancy. Primary polydipsia results in secondary insufficiencies of AVP due to inhibition of AVP secretion by excessive fluid intake. Nephrogenic DI can be genetic or acquired from drug exposure or renal damage.

Table 170-1 Causes of Diabetes Insipidus

Clinical Features   Symptoms include polyuria, excessive thirst, and polydipsia, with a 24-h urine output of >50(mL/kg)/day and a urine osmolality that is less than that of serum (<300 mosmol/kg; specific gravity <1.010). Clinical or laboratory signs of dehydration, including hypernatremia, occur only if the pt simultaneously has a thirst defect or does not have access to water. Other etiologies of hypernatremia are described in Chap. 26.
Diagnosis   DI must be differentiated from other etiologies of polyuria (Chap. 25). Unless an inappropriately dilute urine is present in the setting of serum hyperosmolality, a fluid deprivation test is used to make the diagnosis of DI. This test should be started in the morning, and body weight, plasma osmolality, sodium concentration, and urine volume and osmolality should be measured hourly. The test should be stopped when body weight decreases by 5% or plasma osmolality/sodium exceed the upper limit of normal. If the urine osmolality is <300 mosmol/kg with serum hyperosmolality, desmopressin (0.03 µg/kg SC) should be administered with repeat measurement of urine osmolality 1–2 h later. An increase of >50% indicates severe pituitary DI, whereas a smaller or absent response suggests nephrogenic DI. Measurement of AVP levels before and after fluid deprivation may be required to diagnose partial DI. Occasionally, hypertonic saline infusion may be required if fluid deprivation does not achieve the requisite level of hypertonic dehydration.

Pituitary DI can be treated with desmopressin (DDAVP) subcutaneously (1–2 µg qd-bid), via nasal spray (10–20 µg bid-tid), or orally (100–400 µg bid- tid), with recommendations to drink to thirst. Chlorpropamide has also been used, though caution must be used to avoid hypoglycemia and a disulfuram-like reaction to ethanol. Symptoms of nephrogenic DI may be ameliorated by treatment with a thiazide diuretic and/or amiloride in conjunction with a low-sodium diet, or with prostaglandin synthesis inhibitors (e.g., indomethacin).

Etiology   Excessive or inappropriate production of AVP predisposes to hyponatremia, reflecting water retention. The evaluation of hyponatremia is described in Chap. 26. Etiologies of SIADH include neoplasms (lung, GI, pancreas, thymoma), lung infections, CNS disorders, and drugs (desmopressin, chlorpropamide, vincristine, carbamazepine, phenothiazines, cyclophosphamide, narcotics, tricyclic antidepressants, SSRIs) (Table 170-2).

Table 170-2 Causes of Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Clinical Features   If the hyponatremia develops gradually, it may be asymptomatic. However, if it develops acutely, symptoms of water intoxication may include mild headache, confusion, anorexia, nausea, vomiting, coma, and convulsions. Laboratory findings include low BUN, creatinine, uric acid, and albumin; serum Na <130 mmol/L and plasma osmolality <270 mmol/kg; urine is almost always hypertonic to plasma, and urinary Na+ is usually >20 mmol/L.

Fluid intake should be restricted to 500 mL less than urinary output. In patients with severe symptoms or signs, hypertonic (3%) saline can be infused at £0.05 mL/kg body weight IV per minute, with hourly sodium levels measured until Na increases by 12 mmol/L or to 130 mmol/L, whichever occurs first. However, if the hyponatremia has been present for more than 24–48 h and is corrected too rapidly, saline infusion has the potential to produce central pontine myelinolysis. Demeclocycline (150–300 mg PO tid-qid) or fludrocortisone (0.05–0.2 mg PO bid) may be required to manage chronic SIADH.


For a more detailed discussion, see Robertson, GL: Disorders of the Neurohypophysis, Chap. 329, p. 2052, in HPIM-15.

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