What are the presentation, diagnosis, types, and treatment of Diabetes Insipidus (DI)?

Diabetes Insipidus: Presentation, Diagnosis, Types, and Treatment

Clinical Presentation

Diabetes insipidus presents with hypotonic polyuria (>3 liters/24 hours in adults), polydipsia, and risk of hypernatremic dehydration, with symptoms persisting even during water deprivation. 1

Key Presenting Features:

• Polyuria with inappropriately diluted urine (osmolality <200 mOsm/kg H₂O) combined with high-normal or elevated serum sodium is pathognomonic for diabetes insipidus 2
• Nocturia with night waking is a reliable indicator of organic disease rather than behavioral polydipsia 1
• In infants and children: feeding difficulties, failure to thrive, vomiting, and hypernatremic dehydration 2
• In adults: polydipsia is the predominant symptom at diagnosis 2

Critical Pitfall:

Delayed diagnosis can result in prolonged periods of severe hypertonic dehydration leading to seizures, developmental delay, and cognitive impairment, particularly in children 2

Types of Diabetes Insipidus

Central Diabetes Insipidus (Vasopressin Deficiency)

• Caused by deficiency of arginine vasopressin (AVP) from pituitary gland or hypothalamus dysfunction 3
• Approximately 90% of congenital cases are X-linked (AVPR2 gene mutations on chromosome Xq28), predominantly affecting males 2
• Acquired causes include: craniopharyngioma or germinoma (age <30 years), metastases (age >50 years), head trauma (2% of cases), transsphenoidal surgery (8-9% of cases), and IgG4-related hypophysitis 1
• Responds to desmopressin administration 2, 4

Nephrogenic Diabetes Insipidus (Vasopressin Resistance)

• Results from kidney insensitivity to AVP despite normal hormone levels 2
• Congenital forms: X-linked (AVPR2 mutations, ~90%) or autosomal (AQP2 mutations, <10%) 2
• Acquired causes: lithium intake (most common), Bartter syndrome, distal renal tubular acidosis, nephronophthisis, and apparent mineralocorticoid excess 2
• Does not respond to desmopressin 2, 4

Primary Polydipsia

• Excessive water intake without AVP abnormality, most common in psychiatric patients and health enthusiasts 3
• Responds to water deprivation 2

Gestational Diabetes Insipidus

• Results from increased placental vasopressinase activity 5

Diagnostic Approach

Early genetic testing is strongly recommended when congenital nephrogenic diabetes insipidus is suspected, as it provides definitive diagnosis, avoids potentially harmful diagnostic procedures, and enables precise genetic counseling. 2

Initial Workup:

• Measure serum sodium, serum osmolality, urine osmolality, and urine volume to establish baseline values 6, 4
• Construct comprehensive family history and pedigree to identify familial cases 2
• Perform pituitary MRI to assess for loss of posterior pituitary hyperintensity signal (indicates AVP absence in central DI) and identify structural lesions 1

Plasma Copeptin Measurement:

• Copeptin is released in equimolar 1:1 ratio with AVP and serves as a stable surrogate marker 2
• Baseline plasma copeptin >21.4 pmol/L is diagnostic for nephrogenic DI in adults 2
• Copeptin <21.4 pmol/L requires testing for AVP deficiency (central DI) versus primary polydipsia 2, 6, 4

Confirmatory Testing (when genetic testing unavailable or copeptin <21.4 pmol/L):

• Hypertonic saline infusion test with copeptin measurement 2, 4
• Arginine stimulation test with copeptin measurement 2, 4
• Water deprivation test (traditional gold standard but potentially harmful, especially in children) 7, 5
• Desmopressin (DDAVP) challenge: response confirms central DI; no response indicates nephrogenic DI 2, 4, 8

Genetic Testing Indications:

Genetic testing should be performed early in suspected congenital cases to avoid unpleasant diagnostic procedures, prevent prolonged dehydration, inform genetic counseling, and identify partial NDI cases with challenging laboratory findings 2

Treatment

Central Diabetes Insipidus

Desmopressin is the first-line treatment for central diabetes insipidus, administered intranasally, orally, or by injection depending on clinical circumstances. 4, 8

Desmopressin Administration:

• Intranasal desmopressin 0.01% solution is indicated for antidiuretic replacement therapy in central cranial diabetes insipidus 8
• Alternative routes (injection, oral) are needed when intranasal delivery is compromised by nasal congestion, discharge, atrophic rhinitis, impaired consciousness, or post-cranial surgery 8
• Monitor serum sodium carefully to avoid hyponatremia, the main treatment complication 4
• Assess treatment efficacy through urine osmolality, urine production, and weight gain 4

Fluid Management:

• Allow ad libitum fluid access to prevent dehydration, hypernatremia, growth failure, and constipation 2, 6, 4
• Patients capable of self-regulation should rely on thirst sensation rather than prescribed fluid amounts, as osmosensors are more sensitive than medical calculations 2, 6

Nephrogenic Diabetes Insipidus

Treatment of nephrogenic DI is particularly challenging and requires specialized multidisciplinary expertise, especially in infants who cannot express thirst. 2

Fluid Management:

• Provide ad libitum fluid access for all patients with NDI 2
• For infants or cognitively impaired patients unable to self-regulate: offer water frequently beyond regular intake with close monitoring of weight, fluid balance, and biochemistry 2
• During prolonged fasting (>4 hours): administer intravenous 5% dextrose in water at maintenance rate, with regular blood glucose monitoring to prevent hyperglycemia-induced osmotic diuresis 2

Nutritional Support:

• Ensure adequate caloric intake and consider tube feeding when necessary 2

Monitoring and Follow-up

Regular monitoring is crucial for all diabetes insipidus patients to detect complications and optimize treatment. 6

• Monitor serum electrolytes (sodium, potassium, chloride), urine volume and osmolality, and body weight regularly 6
• Perform urinary tract ultrasound every 2-3 years to detect potential complications 6
• In idiopathic central DI, maintain close follow-up as it may be the first sign of underlying pathology 5
• Watch for decreased responsiveness or shortened duration of effect (may occur after >6 months), which may be due to local peptide inactivation rather than antibody development 8