DIABETES INSIPIDUS

DIABETES INSIPIDUS - Keith Medeiros, MD
BASICS
DESCRIPTION
• Defective regulation of water balance secondary to decreased pituitary secretion of (central DI), or failure of response to (nephrogenic DI), vasopressin
• System(s) Affected: Endocrine/Metabolic
GENERAL PREVENTION
• Avoid marked increase in water loss.
• Take fluids as dictated by thirst with no water restriction.
EPIDEMIOLOGY
Incidence
18.3% following transsphenoidal microsurgery (1)
Prevalence
• Vasopressin deficiency may occur at any age, including infancy and childhood.
• Nephrogenic diabetes insipidus (DI) is usually manifest in infancy.
• Nephrogenic DI is encountered in males with rare exception, reflecting its X-linked recessive mode of inheritance.
RISK FACTORS
• Intracranial neoplasm
• Following surgery
• Patients using lithium
Genetics
• Central DI
- Familial cases of vasopressin deficiency have been reported (commonly autosomal dominant; >20 mutations have been identified), but the disease is usually isolated, and often secondary to other disorders.
• Nephrogenic DI
- Most common is an X-linked defect in the V2 receptor that binds ADH.
- Autosomal dominant or recessive defects in the aquaporin-2 gene that encodes an ADH responsive water channel.
PATHOPHYSIOLOGY
• Central DI
- Inadequate secretion of vasopressin may be due to loss of or malfunction of the neurosecretory neurons that make up the neurohypophysis (posterior pituitary) and the pituitary stalk.
• Nephrogenic DI
- Insensitivity to vasopressin
- A disorder of renal tubular function resulting in inability to respond to vasopressin in absorption of water
ETIOLOGY
• Central DI
- Inadequate secretion of vasopressin due to pathologic condition, which may be idiopathic or familial
 Trauma
 Neurosurgery
 Tumors (craniopharyngioma, lymphoma, metastasis)
 Idiopathic
 Infections (meningitis, encephalitis)
 Granulomas (sarcoid, histiocytosis)
 Vascular disorders
• Nephrogenic DI (insensitivity to vasopressin):
- Genetic defect in resorption of water in renal tubule (collecting ducts)
- Drugs (2)[A]
 Lithium, demeclocycline, dexamethasone, dopamine, ifosfamide, ofloxacin, amphotericin B, orlistat
- Hypercalcemia
- Hypokalemia
ASSOCIATED CONDITIONS
• Potassium depletion
• Chronic hypercalcemia
• Tumors
• Infection
- Encephalitis
- Tuberculosis
- Syphilis
• Xanthomatosis
• Pyelonephritis
• Renal amyloidosis
• Sjogren syndrome
• Sickle cell anemia
• Wolfram syndrome (DIDMOAD: DI, diabetes mellitus, optic atrophy, and deafness)

DIAGNOSIS
SIGNS AND SYMPTOMS
• Thirst/polydipsia (with a particular preference for cold or iced drinks)
• Polyuria
• Nocturia
• Dehydration
• Headache
• Visual disturbance
History
• Rate of onset of polydipsia is more rapid in central DI versus nephrogenic
• Family history of polyuria
TESTS
• Water restriction test to evaluate the ability to concentrate urine
- Water is withheld and urine and plasma osmolality are measured at hourly intervals.
- A rise in urine osmolality indicates an intact ADH response.
- A rise in plasma osmolality or stable urine osmolality indicates poor ADH response.
- Perform the test during the day, not overnight to avoid serious volume depletion or hypernatremia.
- If the results support the diagnosis, desmopressin should be administered to test renal concentrating ability.
• Urine/plasma osmolal ratio and plasma vasopressin concentrations
- Results may be difficult to interpret: Low ratios may be found in patients with primary polydipsia
Lab
• Urine electrolyte levels
- Hypernatremia (usually 150 mEq/L because of increased thirst)
• Urine osmolality
- Inability to concentrate urine (measure by osmolality, rather than specific gravity)
- Hypokalemia and hypercalcemia alter ability to concentrate urine
• Urinary glucose
- Rule out diabetes mellitus
• Plasma vasopressin or urinary vasopressin following osmotic stimulus, such as fluid restriction or administration of hypertonic saline
• Drugs that may alter lab results: Lithium, demeclocycline, and methoxyflurane may produce vasopressin insensitivity.
• Disorders that may alter lab results: Hypokalemia and hypercalcemia alter ability to concentrate urine
Imaging
If the diagnosis of DI is made, appropriate studies for cause, including imaging of the brain must be performed.
Diagnostic Procedures/Surgery
Fluid deprivation to concentrate urine
Pathological Findings
Degeneration and death of neurosecretory neurons in the neurohypophysis
DIFFERENTIAL DIAGNOSIS
• Diabetes mellitus and other causes of polydipsia and polyuria
• Increased solute load for excretion as occurs with high salt intake
• Psychogenic polydipsia (ultimately impairs vasopressin secretion)
TREATMENT
GENERAL MEASURES
• Control fluid balance and prevent dehydration
• Check weight daily.
• Provide good skin and mouth care.
• Nephrogenic DI
- Correct hypercalcemia and hypokalemia and discontinue causative medications (3)[A].
Diet
• Normal, with free access to fluids
• Young infants with nephrogenic DI may benefit from low-solute formula.
• A low-sodium, low-protein diet may reduce urine output in nephrogenic DI
Activity
Not restricted
MEDICATION (DRUGS)
First Line
• Central (vasopressin deficient) DI
- Desmopressin (DDAVP) (a derivative of vasopressin)
 Intranasally 1- 2 times a day in dosage necessary to control polyuria or polydipsia (usually 5-20 ug)
 Orally starting at 100 ug 2-4 times a day on an empty stomach titrated to 200-600 ug 2-4 times a day (4)[B]
• Nephrogenic DI
- Hydrochlorothiazide 25 mg once or b.i.d.
- Amiloride can be added to HCTZ for an additive effect.
• Contraindications: Use desmopressin with caution in the immediate postoperative period for intracranial lesions because of possible cerebral edema.
• Precautions: An overdose of desmopressin may produce water intoxication and hyponatremia in patients with excessive water intake.
Second Line
• Central DI
- Chlorpropamide (Diabinese): 125-250 mg once or b.i.d. enhances renal response to ADH.
- Clofibrate (Atromid-S): 500 mg q6h may increase ADH release.
- Hydrochlorothiazide: 25 mg once or b.i.d.
• Precautions: Chlorpropamide is an oral hypoglycemic agent that can cause hypoglycemia in elevated doses.
FOLLOW-UP
• Initial diagnosis and management may require hospitalization.
• Continuing care is provided on an outpatient basis with self-medication.
PROGNOSIS
• Most reversible cases of nephrogenic DI are caused by medications, and patient symptoms improve with removal of the offending agent (2)[A]
- Lithium may cause irreversible DI (2)[A]
• Generally good prognosis depending on underlying disorder
COMPLICATIONS
• Dilatation of the urinary tract has been observed (probably secondary to large volume of urine).
• Complications of the primary disease (tumor histiocytosis, etc.) should be anticipated.
• In congenital nephrogenic DI, an associated retardation of mental development may occur in some patients (cause undetermined).
• Without treatment, dehydration can lead to confusion, stupor, and coma.
• Subnormal growth rate
PATIENT MONITORING
• Regular follow-up at 2-3-week intervals initially and 3-4 months later
• Adjust treatment on the basis of urine and electrolyte concentrations and the patient's symptoms.
REFERENCES
1. Nemergut EC, Zuo Z, Jane JA Jr, Laws ER Jr. Predictors of diabetes insipidus after transsphenoidal surgery: a review of 881 patients. J Neurosurg 2005 Sep;103(3):448-454.
2. Garofeanu CG, Weir M, Rosas-Arellano MP, et al. Causes of reversible nephrogenic diabetes insipidus: a systematic review. Am J Kidney Dis 2005 Apr;45(4):626-637. Review.
3. Makaryus AN, McFarlane SI. Diabetes insipidus: diagnosis and treatment of a complex disease. Cleve Clin J Med 2006 Jan;73(1):65-71.
4. Fukuda I, Hizuka N, Takano K. Oral DDAVP is a good alternative therapy for patients with central diabetes insipidus: experience of five-year treatment. Endocr J 2003 Aug;50(4):437-443.