What are the causes of diabetes insipidus?

Causes of Diabetes Insipidus

Diabetes insipidus (DI) is primarily caused by either inadequate production/secretion of antidiuretic hormone (central DI) or impaired renal response to ADH (nephrogenic DI), with additional forms including gestational DI and primary polydipsia. 1, 2

Main Categories of Diabetes Insipidus

1. Central (Neurogenic) Diabetes Insipidus

Central DI results from inadequate production or secretion of antidiuretic hormone (ADH/vasopressin) from the posterior pituitary gland. Causes include:

• Acquired causes:

  • Brain tumors (particularly craniopharyngiomas)
  • Neurosurgical procedures
  • Head trauma
  • Pituitary/hypothalamic inflammation
  • Infiltrative diseases (sarcoidosis, histiocytosis)
  • Vascular lesions (aneurysms, Sheehan syndrome)
  • Infections (meningitis, encephalitis)

• Genetic causes:

  • Wolfram syndrome (autosomal recessive disorder with diabetes insipidus, diabetes mellitus, optic atrophy, and neural deafness) 3
  • Familial forms of central DI

• Idiopathic: In approximately 30% of cases, no clear cause is identified 1

2. Nephrogenic Diabetes Insipidus

Nephrogenic DI occurs due to kidney resistance to ADH action. Causes include:

• Genetic causes:

  • X-linked recessive mutations in AVPR2 gene (90% of hereditary cases) 4
  • Autosomal recessive or dominant mutations in AQP2 gene (10% of hereditary cases) 4

• Acquired causes:

  • Medications:
    • Lithium (most common drug cause)
    • Demeclocycline
    • Amphotericin B
    • Certain antibiotics
  • Electrolyte disorders:
    • Hypercalcemia
    • Hypokalemia
  • Kidney diseases:
    • Polycystic kidney disease
    • Chronic kidney disease
    • Post-obstructive uropathy
  • Pregnancy (rare)

3. Gestational Diabetes Insipidus

• Caused by increased metabolism of ADH by placental vasopressinase during pregnancy 5
• Usually resolves after delivery

4. Primary Polydipsia

While not technically diabetes insipidus, primary polydipsia presents with similar symptoms:

• Excessive fluid intake suppresses ADH secretion
• Often associated with psychiatric disorders
• Can be habit-related or due to hypothalamic dysfunction affecting thirst regulation 5

Less Common Causes

• Drug or Chemical-Induced: Various medications can impair insulin secretion or action, potentially precipitating diabetes insipidus in susceptible individuals 3

• Diseases of the Exocrine Pancreas: Processes that diffusely injure the pancreas (pancreatitis, trauma, infection, pancreatectomy) can lead to diabetes, though this more commonly refers to diabetes mellitus 3

• Combined Forms: Some patients may present with features of both central and nephrogenic DI, requiring careful diagnostic workup 1

Diagnostic Considerations

When evaluating a patient with polyuria and polydipsia, it's critical to distinguish between the different forms of DI:

• Central DI: Urine osmolality <200 mOsm/kg, serum sodium >145 mmol/L, significant response to desmopressin
• Nephrogenic DI: Urine osmolality <200 mOsm/kg, serum sodium >145 mmol/L, minimal/no response to desmopressin
• Primary Polydipsia: Variable urine osmolality (can exceed 300 mOsm/kg after water deprivation), normal or low serum sodium, minimal response to desmopressin 1

Clinical Pearls

• Always consider diabetes insipidus in patients presenting with unexplained polyuria and polydipsia
• MRI of the brain is essential in central DI to identify structural causes
• Genetic testing should be considered in familial cases, particularly for nephrogenic DI
• The water deprivation test followed by desmopressin administration remains the gold standard for diagnosis, though newer markers like copeptin show promise 2
• Recent expert groups have proposed renaming diabetes insipidus as "vasopressin deficiency" (central DI) or "vasopressin resistance" (nephrogenic DI) to avoid confusion with diabetes mellitus 6