Diabetes Insipidus & SIADH
A high-yield Step 1/Step 2 CK lesson contrasting diabetes insipidus (too little ADH effect → dilute polyuria, hypernatremia) with SIADH (too much ADH → euvolemic hyponatremia), walking pathophysiology, dynamic testing, buzzword vignettes, a labs comparison table, and next-best-step management including sodium-correction limits.
The ADH Axis: Two Opposite Failures
Antidiuretic hormone (ADH / arginine vasopressin) is synthesized in the hypothalamus (supraoptic and paraventricular nuclei) and released from the posterior pituitary in response to rising plasma osmolality or falling blood volume. It binds V2 receptors in the renal collecting duct, inserting aquaporin-2 channels so free water is reabsorbed and urine is concentrated.
Two classic disorders sit at opposite poles of this axis:
- Diabetes insipidus (DI) = too little ADH effect → the kidney cannot concentrate urine → dilute polyuria + hypernatremia.
- SIADH = too much ADH → free water retained → euvolemic hyponatremia with inappropriately concentrated urine.
Note the 2022 renaming: central DI → AVP deficiency (AVP-D), nephrogenic DI → AVP resistance (AVP-R); boards still write "DI." The single fastest triage: check the serum sodium — high points to DI, low points to SIADH.
- Core defect: central DI = decreased ADH production; nephrogenic DI = renal resistance to ADH.
- Central causes: idiopathic/autoimmune, pituitary surgery or trauma, craniopharyngioma / germinoma, infiltrative disease (sarcoidosis, Langerhans cell histiocytosis).
- Nephrogenic causes: lithium (classic), hypercalcemia, hypokalemia, X-linked V2-receptor mutation, chronic kidney disease.
- Labs: high-normal/high serum Na⁺, serum osm >295, urine osm <300 (often <200), low urine specific gravity.
- Water deprivation test: urine stays dilute despite rising serum osm; then give desmopressin (DDAVP):
- Central DI → urine osm rises >50% (concentrates).
- Nephrogenic DI → little/no response.
- MRI: loss of the posterior pituitary "bright spot" on T1 in central DI.
- Copeptin (stable AVP surrogate): low stimulated copeptin supports central DI; high baseline supports nephrogenic.
- Mechanism: inappropriate ADH → free-water retention → dilutional, euvolemic hyponatremia (mild volume expansion, no edema).
- Diagnostic criteria (all needed): serum osm <275, urine osm >100, urine Na⁺ >30–40, clinical euvolemia, normal thyroid + adrenal + renal function, and no diuretics.
- Supportive labs: low BUN and low uric acid (volume expansion + increased clearance).
- Classic causes (buzzwords):
- Small cell lung carcinoma — ectopic ADH.
- CNS: stroke, hemorrhage, meningitis, head trauma.
- Pulmonary: pneumonia, TB.
- Drugs: carbamazepine, SSRIs, cyclophosphamide, MDMA/ecstasy, chlorpropamide, antipsychotics.
- Post-op pain / nausea.
- Key mimic: cerebral salt wasting after CNS injury is hypovolemic (treat with salt + volume); SIADH is euvolemic (treat with water restriction). Volume status is the discriminator.
Labs at a Glance: DI vs SIADH
| Parameter | Central DI | Nephrogenic DI | SIADH |
|---|---|---|---|
| Serum Na⁺ | High / high-normal | High / high-normal | Low |
| Serum osm | High (>295) | High (>295) | Low (<275) |
| Urine osm | Low (<300) | Low (<300) | High (>100) |
| Urine Na⁺ | Variable | Variable | High (>30–40) |
| Volume status | Eu-/hypovolemic | Eu-/hypovolemic | Euvolemic |
| ADH level | Low | High / normal | High |
| DDAVP response | Concentrates urine | No response | n/a |
| First-line Rx | Desmopressin | Treat cause; thiazide, amiloride, NSAIDs | Fluid restriction |
A 42-year-old on long-term lithium for bipolar disorder reports 6 weeks of intense thirst and >5 L/day of dilute urine. Serum Na⁺ 148, serum osm 300, urine osm 150, specific gravity 1.003. He keeps producing dilute urine after overnight water deprivation, and urine osmolality does not rise after desmopressin.
- Diagnosis: lithium-induced nephrogenic DI (AVP resistance).
- Best next step: reduce/stop lithium if psychiatrically feasible and start amiloride (blocks ENaC → limits lithium entry into principal cells); a thiazide plus low-salt/low-protein diet also cuts urine output.
- Contrast: if DDAVP had concentrated the urine (>50% rise), the answer would be central DI → desmopressin.
- Pitfall: correct the hypernatremia slowly to avoid cerebral edema.
A 64-year-old smoker with weight loss has Na⁺ 118, serum osm 250, urine osm 480, urine Na⁺ 60. He is clinically euvolemic; TSH and morning cortisol are normal; he takes no diuretics. He is confused but not seizing. CXR shows a hilar mass.
- Diagnosis: SIADH from small cell lung carcinoma (ectopic ADH).
- Best next step (symptomatic, Na⁺ <120): cautious 3% hypertonic saline (e.g., 100–150 mL boluses) with frequent Na⁺ checks. Fluid restriction is first-line for mild/chronic disease; second-line chronic options are tolvaptan (V2 antagonist), salt tablets ± loop diuretic, or urea.
- Correction limit: raise serum Na⁺ ≤8 mEq/L per 24 h to avoid osmotic demyelination.
- Definitive: treat the underlying malignancy.
Sodium Correction & the Post-Op Trap
Correction speed is a board favorite. For chronic hyponatremia (SIADH), overly rapid correction causes osmotic demyelination syndrome (ODS / central pontine myelinolysis) — limit the rise to ≤8 mEq/L per 24 h (many target ~6). It presents days later with dysarthria, dysphagia, and a "locked-in" quadriparesis. Conversely, chronic hypernatremia (DI) must be lowered slowly to avoid cerebral edema.
Triple-phase response after pituitary/hypothalamic surgery: transient central DI (first several days) → an antidiuretic / SIADH phase (roughly days 4–10, from release of stored ADH by degenerating neurons) → often permanent DI. This is why post-op sodium swings both ways — track Na⁺ and urine output serially rather than reflexively treating one value.
Nephrogenic DI therapy logic: paradoxically, thiazides induce mild volume contraction → more proximal Na⁺/water reabsorption → less free water delivered distally; NSAIDs (e.g., indomethacin) reduce prostaglandin antagonism of ADH to further cut urine output; amiloride is preferred for lithium toxicity.
"From low to high, the pons will die; from high to low, the brain will blow."
- Low → high too fast: correcting hyponatremia (low Na⁺) rapidly → osmotic demyelination of the pons (central pontine myelinolysis).
- High → low too fast: correcting hypernatremia (high Na⁺) rapidly → cerebral edema ("the brain blows").
Directional check for the disorders themselves:
- DI = Dilute urine + Increased sodium.
- SIADH = concentrated urine + low sodium.
Practice Endocrine now
Board-style questions, spaced-repetition flashcards, and a Socratic AI tutor — free to start.