Diabetes Insipidus for the ABIM

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Diabetes Insipidus (DI) for the American Board of Internal Medicine

Deficiency or Resistance to ADH: Diabetes insipidus (DI) results from either insufficient production of antidiuretic hormone (ADH) (central DI) or resistance to ADH's action in the kidneys (nephrogenic DI).
Impaired Water Reabsorption: ADH normally promotes water reabsorption in the renal collecting ducts. In DI, reduced or absent ADH activity leads to the inability to concentrate urine, resulting in the excretion of large volumes of dilute urine.
Polyuria and Polydipsia: The inability to retain water causes excessive urination (polyuria), and the resultant dehydration stimulates thirst (polydipsia) in an attempt to maintain water balance.

Central DI: Results from inadequate ADH production or secretion due to hypothalamic or pituitary dysfunction.
Causes:
Idiopathic: Most common cause; thought to involve autoimmune destruction of ADH-producing cells.
Trauma: Head injuries, surgical procedures, or tumors affecting the hypothalamus or pituitary gland.
Neurosurgery: Postoperative complication after surgery near the pituitary gland.
Infiltrative Diseases: Sarcoidosis, histiocytosis X, and tuberculosis can damage the hypothalamic-pituitary axis.
Nephrogenic DI: Results from renal resistance to ADH, despite normal or elevated levels of the hormone.
Causes:
Genetic: Mutations in the V2 receptor or aquaporin-2 channel.
Medications: Lithium is the most common drug causing nephrogenic DI.
Hypercalcemia and Hypokalemia: Both can impair the renal response to ADH.
Chronic Kidney Disease (CKD): Can reduce the kidney's ability to concentrate urine.

Polyuria: Excessive urination (>3 liters/day). In severe cases, urine output can reach 20 liters/day.
Polydipsia: Intense thirst and increased water intake due to the body's attempt to compensate for water loss.
Dehydration: If fluid intake is insufficient, dehydration may develop, leading to dry mucous membranes, hypotension, and tachycardia.
Nocturia: Waking up multiple times at night to urinate.
Fatigue and Electrolyte Imbalances: Chronic polyuria can cause electrolyte abnormalities, such as hypernatremia if fluid intake is not maintained.

Clinical Suspicion: Diagnosis is suggested by the presence of polyuria, polydipsia, and dilute urine.
Water Deprivation Test:
Purpose: To differentiate between central and nephrogenic DI and primary polydipsia.
Procedure: The patient is deprived of water for a specified period, followed by the measurement of urine osmolality and ADH levels.
Central DI: Urine remains dilute (low osmolality) after water deprivation, but concentrates after desmopressin administration.
Nephrogenic DI: Urine remains dilute even after desmopressin.
Primary Polydipsia: Urine osmolality increases after water deprivation due to intact ADH secretion.
Serum and Urine Osmolality:
Serum Osmolality: Typically elevated (>295 mOsm/kg) due to free water loss.
Urine Osmolality: Low (<300 mOsm/kg) in DI due to inability to concentrate urine.
Plasma Sodium: Hypernatremia may occur in cases of inadequate water intake.
ADH Levels: Low or undetectable in central DI; normal to high in nephrogenic DI.

Primary Polydipsia: Characterized by excessive water intake leading to dilute urine. Unlike DI, these patients have normal ADH function, and urine can concentrate when water intake is restricted.
Psychogenic Polydipsia: A form of primary polydipsia, often seen in patients with psychiatric disorders, leading to voluntary excessive water intake.
Diuretic Use: Chronic use of diuretics can mimic polyuria.

Desmopressin (DDAVP): A synthetic analog of ADH is the first-line treatment. It can be administered orally, intranasally, or subcutaneously. The goal is to replace the deficient ADH, reducing polyuria and normalizing serum sodium.
Monitoring and Dose Adjustment: Patients on desmopressin need regular monitoring of serum sodium levels and fluid intake to prevent water intoxication and hyponatremia.
Treatment of Underlying Cause: If central DI is secondary to a tumor, trauma, or infiltrative disease, treating the underlying condition may improve ADH secretion.

Correction of the Underlying Cause: If possible, removing or addressing the cause (e.g., discontinuing lithium or correcting hypercalcemia) can reverse nephrogenic DI.
Thiazide Diuretics: Paradoxically, thiazides reduce polyuria in nephrogenic DI by inducing mild hypovolemia, which leads to increased sodium and water reabsorption in the proximal tubules.
Low-Sodium Diet: Reduces the osmotic load on the kidneys, helping to decrease urine output.
Amiloride: Particularly useful for lithium-induced nephrogenic DI, as it blocks lithium's entry into the renal cells, mitigating its effect on ADH resistance.

Hypernatremia: If water intake does not match water loss, hypernatremia can develop, leading to confusion, seizures, and coma.
Dehydration: Severe dehydration can result in hypotension, tachycardia, and shock if not addressed.
Water Intoxication: Overcorrection with desmopressin can result in excessive water retention, leading to hyponatremia, confusion, and seizures.

Central DI: Most cases respond well to desmopressin, and patients can lead a normal life with adequate treatment and monitoring.
Nephrogenic DI: Prognosis depends on the underlying cause. Genetic nephrogenic DI is lifelong, but symptoms can be managed. Acquired cases may resolve with correction of the underlying cause.

Key Points

Central DI is due to insufficient ADH production, while nephrogenic DI results from renal resistance to ADH.
Both forms cause polyuria, polydipsia, and inability to concentrate urine, leading to dehydration and hypernatremia.

Central DI is commonly caused by trauma, tumors, or idiopathic reasons.
Nephrogenic DI can result from medications (e.g., lithium), genetic mutations, hypercalcemia, or kidney disease.

Water deprivation test differentiates central from nephrogenic DI and primary polydipsia.
Serum osmolality is high, urine osmolality is low, and hypernatremia may occur.

Central DI is treated with desmopressin (DDAVP).
Nephrogenic DI management includes thiazide diuretics, low-sodium diet, and correction of underlying causes.

Hypernatremia and dehydration are serious risks if DI is not treated properly.
Overcorrection with desmopressin can lead to water intoxication and hyponatremia.