- Diabetes Insipidus
- Etiology
- Clinical Features
- Diagnosis
- Syndrome of Inappropriate Antidiuretic Hormone (SIADH)
- Etiology
- Clinical Features
The neurohypophysis, or 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.
Diabetes insipidus (DI) results from insufficient AVP production by the hypothalamus or from impaired AVP action in the kidney. 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 acquired (head trauma; neoplastic or inflammatory conditions affecting the hypothalamus/posterior pituitary), congenital, and genetic disorders, but almost half of cases are idiopathic. In gestational DI, increased metabolism of plasma AVP by an aminopeptidase (vasopressinase) produced by the placenta leads to a relative deficiency of AVP during pregnancy. Primary polydipsia results in secondary insufficiency of AVP due to physiologic inhibition of AVP secretion by excessive fluid intake. There are three main types: (1) dipsogenic DI with inappropriate thirst; (2) psychogenic DI often associated with psychosis or obsessive compulsive disorders; and (3) iatrogenic DI often caused by efforts to consume excess fluids for presumed health benefits. Nephrogenic DI is caused by AVP resistance at the level of the kidney; it can be genetic or acquired from drug exposure (lithium, demeclocycline, amphotericin B), metabolic conditions (hypercalcemia, hypokalemia), or renal damage.
Symptoms include polyuria, excessive thirst, and polydipsia, with a 24-h urine output of >50 mL/kg per day and a urine osmolality that is less than that of serum (<300 mosmol/kg; specific gravity <1.010). DI can be partial or complete; in the latter case the urine is maximally diluted (<100 mosmol/kg) and the daily urine output can reach 10-20 L. Clinical or laboratory signs of dehydration, including hypernatremia, occur only if the pt simultaneously has a thirst defect (not uncommon in pts with CNS disease) or does not have access to water. Other etiologies of hypernatremia are described in Chap. 1 Electrolytes.
DI must be differentiated from other etiologies of polyuria (Chap. 48 Azotemia and Urinary Abnormalities). 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 with careful supervision to avoid dehydration. Body weight, plasma osmolality, serum sodium, and urine volume and osmolality should be measured hourly. The test should be stopped when body weight decreases by 5% or plasma osmolality/sodium exceeds 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 helpful to distinguish central and nephrogenic DI. If AVP is normal or elevated (>1 pg/mL) and the concurrent urine osmolarity is low (<300 mosmol/L), the pt has nephrogenic DI and the only additional evaluation required is to determine the cause. Occasionally, hypertonic saline infusion may be required if fluid deprivation does not achieve the requisite level of hypertonic dehydration, but this should be administered with caution.
| TREATMENT | ||
Diabetes InsipidusPituitary DI can be treated with desmopressin (DDAVP) subcutaneously (1-2 µg once or twice per day), via nasal spray (10-20 µg two or three times a day), or orally (100-400 µg two or three times a day), with recommendations to drink to thirst. 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). |
Syndrome of Inappropriate Antidiuretic Hormone (SIADH) 
Excessive or inappropriate production of AVP predisposes to hyponatremia, reflecting water retention. The evaluation of hyponatremia is described in Chap. 1 Electrolytes. Etiologies of SIADH include neoplasms, lung infections, CNS disorders, and drugs (Table 172-1 Causes of Syndrome of Inappropriate Antidiuretic Hormone (SIADH)).
If hyponatremia develops gradually, it may be asymptomatic until it reaches a severe stage. 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 meq/L and plasma osmolality <270 mosmol/kg; urine is not maximally diluted and frequently hypertonic to plasma, and urinary Na+ is usually >20 mmol/L.
| TREATMENT | ||
SIADHFluid intake should be restricted to 500 mL less than urinary output. In pts 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 meq/L or to 130 meq/L, whichever occurs first. However, if the hyponatremia has been present for >24-48 h and is corrected too rapidly, saline infusion has the potential to produce central pontine myelinolysis, a serious, potentially fatal neurologic complication caused by osmotic fluid shifts. Vasopressin antagonists (conivaptan, tolvaptan) are now available. Conivaptan has been approved for short-term, in-hospital IV treatment of SIADH. It should be given as a loading dose of 20 mg IV over 30 min followed by a continuous infusion of 20 mg over 24 h. Tolvaptan can be given orally starting at a dose of 15 mg PO and increasing to 30 mg or 60 mg at 24-h intervals depending on the effect. With either approach, fluid intake should be restricted to less than urine output. Regulating fluid intake so that it under-replaces urine output by 5 mL/kg body weight per hour will raise serum sodium at a rate of about 1% an hour. In any event, serum sodium should be checked every 2-4 hours to ensure it is not raised faster than ≥1 mEq/L per hour the lower limit of normal. In addition to fluid restriction, the best approach for the treatment of chronic SIADH is the administration of oral tolvaptan, a selective V2 antagonist that increases urinary water excretion by blocking the antidiuretic effect of AVP. Other options include demeclocycline, 150-300 mg PO tid or qid, or fludrocortisone, 0.05-0.2 mg PO bid. The effect of the demeclocycline manifests in 7-14 days and is due to induction of a reversible form of nephrogenic DI. The effect of fludrocortisone also requires 1-2 weeks and is partly due to increased retention of sodium and possibly inhibition of thirst. It also increases urinary potassium excretion, which may require replacement through dietary adjustments or supplements and may induce hypertension. |