What are the steps to diagnose diabetes insipidus?

Diagnosis of Diabetes Insipidus

The diagnosis of diabetes insipidus requires a stepwise approach starting with measurement of serum sodium, serum osmolality, and urine osmolality, followed by genetic testing in suspected nephrogenic diabetes insipidus cases or specialized testing such as water deprivation or hypertonic saline infusion with copeptin measurement for central diabetes insipidus. 1

Initial Diagnostic Evaluation

Clinical Presentation

• Suspect diabetes insipidus in:
  • Infants/children with polyuria, polydipsia, failure to thrive, and hypernatraemic dehydration
  • Adults with unexplained polyuria and polydipsia 1

First-line Laboratory Tests

1. Serum sodium measurement
2. Serum osmolality
3. Urine osmolality

The detection of inappropriately diluted urine (urinary osmolality <200 mOsm/kg H₂O) in combination with high-normal or elevated serum sodium is pathognomonic for diabetes insipidus (either nephrogenic or central) 1

Differentiating Types of Diabetes Insipidus

Central vs. Nephrogenic Diabetes Insipidus

• Central DI: Deficiency of arginine vasopressin (AVP) from the pituitary/hypothalamus
• Nephrogenic DI: Resistance to AVP in the kidneys
• Primary polydipsia: Excessive water intake despite normal AVP secretion and action 2

Genetic Testing

• Genetic testing is strongly recommended as first-line for suspected nephrogenic diabetes insipidus (NDI) 1
  • X-linked form (90% of cases): Pathogenic variants in AVPR2 gene
  • Autosomal forms (<10% of cases): Pathogenic variants in AQP2 gene

Advanced Diagnostic Testing

If genetic testing is unavailable or results are inconclusive:

1. Water Deprivation Test (traditional approach)

   • Patient is deprived of water for up to 17 hours
   • Limitations: Long duration, cumbersome for patients, limited diagnostic accuracy 3

2. Hypertonic Saline Infusion with Copeptin Measurement (newer approach)

   • More accurate than water deprivation test
   • A copeptin level of 4.9 pmol/L after stimulation differentiates central DI from primary polydipsia
   • Requires close sodium monitoring every 30 minutes
   • Common side effects 3

3. Arginine Stimulation with Copeptin Measurement (newest approach)

   • Simpler and better tolerated than hypertonic saline
   • Arginine significantly stimulates copeptin release 3

Imaging Studies

MRI of the Sella/Brain

• MRI with and without IV contrast using high-resolution pituitary or skull base protocols is the preferred imaging modality for suspected central diabetes insipidus 1
• Key findings to look for:
  • Absence of T1 signal hyperintensity of normal neurosecretory granules
  • Abnormalities of the hypothalamic-neurohypophyseal axis
  • Ectopic posterior pituitary gland
  • Mass lesions affecting the pituitary stalk or hypothalamic-pituitary axis 1

CT Imaging

• Less preferred than MRI but can be used if MRI is contraindicated
• Can detect solid lesions of the suprasellar cistern and infiltrative lesions of the pituitary stalk
• May miss cystic tumors
• Requires multiplanar reconstructions with thin sections and soft-tissue window settings 1

Diagnostic Algorithm

1. Initial evaluation: Serum sodium, serum osmolality, urine osmolality
2. If inappropriately diluted urine with high-normal/elevated serum sodium:
   • For suspected nephrogenic DI: Proceed to genetic testing for AVPR2 and AQP2 variants
   • For suspected central DI: Proceed to MRI sella/brain
3. If genetic testing is unavailable or inconclusive:
   • Perform hypertonic saline infusion with copeptin measurement OR
   • Perform arginine stimulation with copeptin measurement OR
   • Perform water deprivation test (less preferred)
4. If central DI is confirmed: Evaluate for underlying causes (tumors, inflammatory processes, trauma, etc.)

Important Considerations

• Genetic testing can avoid unpleasant, challenging, and potentially harmful diagnostic procedures like the desmopressin test or water deprivation test 1
• Early diagnosis prevents prolonged, unrecognized periods of severe hypertonic dehydration, which can result in seizures, developmental delay, and cognitive impairment 1
• Desmopressin nasal spray is indicated for central diabetes insipidus but is ineffective for nephrogenic diabetes insipidus 4
• Random blood glucose testing has limited sensitivity (39-55%) for diabetes mellitus diagnosis and should not be confused with diabetes insipidus testing 1

By following this systematic approach, clinicians can accurately diagnose diabetes insipidus, determine its type, and initiate appropriate management to prevent complications and improve patient outcomes.