CENTRAL DIABETES INSIPIDUS (DI)

Definition and Pathophysiology

• Diabetes Insipidus: Large volume of tasteless (insipid) urine.
• Central (Neurogenic) DI: Characterized by decreased release of antidiuretic hormone (ADH) (vasopressin).
  • Results in polydipsia (excessive thirst) and polyuria (excessive urination).
• ADH Deficiency:
  • Usually due to damage/disorders affecting hypothalamic osmoreceptors, supraoptic/paraventricular nuclei, or the superior portion of the supraopticohypophyseal tract.
  • ~90% of vasopressinergic neurons must be destroyed to cause symptomatic DI.
• Posterior Pituitary Role:
  • The posterior pituitary stores, but does not produce ADH.
  • Intrasellar pituitary tumors typically do not cause DI, unless they extend to the hypothalamus or pituitary stalk.

ETIOLOGY

1. Trauma and Surgery
   • Neurosurgery, particularly in the sellar region (craniotomy or transsphenoidal routes).
   • Closed-head trauma or skull fractures can injure the hypothalamic–pituitary region.
2. Tumors
   • Primary or Metastatic (e.g., breast, lung, kidney, lymphoma, leukemia, colon, melanoma).
   • Craniopharyngioma, germinoma (primary) can damage hypothalamus/posterior pituitary.
3. Infiltrative Disorders
   • Langerhans cell histiocytosis (high risk for central DI).
   • Sarcoidosis, Wegener granulomatosis, autoimmune lymphocytic infundibulohypophysitis.
4. Pregnancy
   • Can exacerbate or unmask mild DI due to increased ADH catabolism by placental vasopressinase (cysteine aminopeptidase).
5. Genetic Causes
   • Familial Central DI: Autosomal dominant mutations in the arginine vasopressin (AVP) gene.
     • Misfolded AVP accumulates in the endoplasmic reticulum, causing cell death in supraoptic/paraventricular nuclei.
     • Symptoms usually appear months/years after birth.
   • Wolfram Syndrome (DIDMOAD): Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness.
     • Central DI typically occurs after the onset of diabetes mellitus.

CLINICAL MANIFESTATIONS

1. Sudden Onset of Polyuria and Thirst
   • Patients crave cold liquids, commonly waking at night to urinate and drink ice-cold water.
   • Urine output can range from 3 L/day in mild partial DI to 10–15 L/day in severe cases.
2. Coexisting Pituitary Failure
   • Secondary adrenal insufficiency (low cortisol) can mask DI by:
     • Decreasing renal blood flow and reducing urine output.
     • Causing increased ADH release in partial DI.
   • Glucocorticoid Replacement can unmask DI by reversing these effects, causing a rapid onset of polyuria.

DI FOLLOWING PITUITARY SURGERY OR HEAD TRAUMA

1. Postoperative Central DI
   • Up to 50% of patients experience transient central DI within 24 hours of pituitary surgery, resolving over several days.
   • Permanent DI occurs in <5% of endoscopic transnasal transsphenoidal cases, but can be as high as 30% after transcranial operations or when large tumors (e.g., craniopharyngiomas) involve the hypothalamus.
2. Triphasic Response after Hypothalamic or Posterior Pituitary Damage
   1. Polyuric Phase (Days 1–5): Decreased ADH release due to axon shock and disrupted action potentials.
   2. Antidiuretic Phase (Days 6–12): Gradual release of stored ADH from degenerating posterior pituitary; hyponatremia can occur if fluids are over-administered.
   3. Permanent DI after ADH stores are depleted (if the injury is severe enough).
3. Inappropriate ADH Release
   • In 10–25% of patients, only the second phase occurs (transient inappropriate ADH release), leading to hyponatremia around day 7 post-surgery.
   • Patients may present with headaches, nausea, vomiting, seizures.
   • Fluid Restriction (“drink to thirst only”) for ~2 weeks post-surgery can mitigate this risk.

SUMMARY OF CLINICAL CAUSES

• Trauma: Skull fracture, head injury.
• Tumors: Craniopharyngioma, germinoma, metastatic lesions.
• Infiltrative: Langerhans cell histiocytosis, sarcoidosis, Wegener granulomatosis, lymphocytic infundibulohypophysitis.
• Pregnancy-Related: Increased vasopressinase activity.
• Genetic: Familial central DI (mutations in the AVP gene), Wolfram syndrome (DIDMOAD).

IMPORTANT CONSIDERATIONS

• Unmasking DI
  • Administration of glucocorticoids to a patient with coexisting secondary adrenal insufficiency can precipitate or reveal underlying DI.
• Late or First Presentation
  • Polyuria/polydipsia can be the initial manifestation of metastatic disease in the hypothalamic–pituitary region.
• Imaging
  • Posterior pituitary “bright spot” on MRI can be normal in early stages but may disappear as the disease progresses.