Pathophysiology

Small cell lung cancer (SCLC) example: 1. Neuroendocrine tumor cells produce ADH (arginine vasopressin, AVP) 2. Ectopic ADH secretion → ADH levels inappropriately high for serum osmolality 3. Kidney collecting duct responds to ADH → aquaporin-2 expression ↑ 4. Water reabsorption ↑ in collecting duct 5. Free water retention → dilutional hyponatremia 6. Urine osmolality >serum osmolality (diagnostic for SIADH)

Diagnostic Criteria for SIADH [2]

SIADH diagnosis requires ALL of:

1. Hyponatremia (Na <135 mEq/L)
   └─ Usually mild-moderate (125–135) unless acute or severe

2. Hypo-osmolality (serum osmolality <275 mOsm/kg)
   └─ Measured directly (not calculated)

3. INAPPROPRIATE urine osmolality
   └─ Urine osmolality >serum osmolality (paradoxically high)
   └─ Normal response would be urine osmolality <100 if plasma hypo-osmolar

4. Absence of:
   ├─ Primary polydipsia (excessive water drinking)
   ├─ Recent diuretic use
   ├─ Hypothyroidism (TSH normal)
   ├─ Adrenal insufficiency (cortisol normal)
   └─ Volume depletion (normal/expanded effective circulating volume)

5. No recent IV hypotonic fluids

Acute vs. Chronic SIADH in Cancer

Acute Symptomatic Hyponatremia (Na <120 or Seizure/Coma)

EMERGENCY — requires immediate intervention.

Patient with seizure + severe hyponatremia + SIADH diagnosis
    ↓
IMMEDIATE:
├─ Hypertonic saline (3% NaCl) IV
│  └─ Bolus: 2–4 mL/kg (max 100 mL) over 10–15 min
│  └─ Goal: Increase Na by 4–6 mEq/L rapidly to stop seizure
├─ Seizure management: Benzodiazepines, airway protection
├─ Continuous cardiac monitoring
└─ Continuous serum Na monitoring (recheck q2–4 hr)
    ↓
After acute seizure controlled:
├─ Slower correction rate: 10–12 mEq/L per 24 hours
├─ AVOID rapid correction: Risk of osmotic demyelination syndrome (ODS)
└─ Re-assess underlying cause (chemo? CNS mets? Medications?)
    ↓
Chronic management (see next section)

Key Point: Hypertonic saline is indicated ONLY for symptomatic hyponatremia (seizure/altered mental status). Do NOT use 3% routinely for all SIADH.

Chronic SIADH (Asymptomatic or Mild Symptoms)

Gradual correction is safer; avoid overcorrection.

Tolvaptan Specifics:

TOLVAPTAN (Samsca) — V2-receptor antagonist:

Mechanism: Blocks ADH (vasopressin) V2-receptors in kidney collecting duct
           → decreased aquaporin-2 expression
           → reduced free water reabsorption
           → aquaresis (electrolyte-free water loss)

Dosing:
├─ Start: 7.5 mg PO daily
├─ Titrate: Increase to 15 mg if Na not rising adequately
├─ Max: 30 mg daily (rarely needed)
└─ Monitor: Recheck Na daily × 3–5 days, then every 2–3 days

Efficacy: Increases Na by 5–10 mEq/L in 24–48 hours in 80% of patients

Advantages:
├─ Rapid onset (hours to days)
├─ Effective even if fluid restriction fails
├─ Allows continued oral intake (no dietary restriction)
└─ Oral medication (convenient)

Adverse effects:
├─ Hypernatremia (overcorrection) — monitor Na closely
├─ Thirst (frequent; patient may overcome fluid restriction)
├─ Polydipsia if Na rises too quickly
└─ Cost: ~$200/month; insurance often requires fluid restriction trial first

Monitoring: Daily Na during initiation; target correction 6–12 mEq/L per 24 hr

CAUTION: Tolvaptan can cause rapid Na rise if patient drinks excess water; requires patient compliance

Treating Underlying Cancer

Golden Rule: Treatment of malignancy often resolves SIADH.

• SCLC + SIADH: Chemotherapy (platinum-etoposide) → SIADH often reverses within 2–3 weeks
• CNS metastases + SIADH: Radiation or surgery → resolution if causes hypothalamic dysfunction
• Chemotherapy-induced SIADH: Discontinue causative agent if possible OR continue with active SIADH management (fluid restriction/tolvaptan)

PTHrP-Mediated HCM (Most Common)

PTHrP = PTH-related peptide (88 amino acids; shares N-terminal homology with PTH)

Mechanism: 1. Tumor cells produce PTHrP (mimics PTH biologically but structurally distinct) 2. PTHrP binds PTH1R (PTH-1 receptor) on bone + kidney 3. Bone effects: - Osteoblasts stimulated → RANKL production - RANKL activates osteoclasts → bone resorption - Massive Ca2+ mobilization from bone into blood 4. Renal effects: - ↑ tubular Ca reabsorption - ↓ phosphate reabsorption (causes hypophosphatemia) - Antagonizes PTH/FGF-23 axis 5. Result: Severe hypercalcemia (often >11 mg/dL; can exceed 14–15)

Osteolytic HCM (Breast, Myeloma)

Mechanism: 1. Metastatic tumor infiltration into bone 2. IL-1, TNF-α, IL-6 production by tumor cells 3. RANKL upregulation by osteoblasts 4. Osteoclast activation → bone resorption, local Ca mobilization 5. Note: PTH suppressed (unlike PTHrP-HCM)

Calcitriol-Mediated HCM (Lymphomas)

Mechanism: 1. Lymphoma granulomas (similar to sarcoidosis pathophysiology) 2. Activated macrophages within granulomas express 1α-hydroxylase 3. Increased conversion of 25-vitamin D → 1,25-vitamin D (active form) 4. Intestinal Ca absorption ↑↑ 5. PTH suppressed (feedback inhibition)

Acute Severe Hypercalcemia (Ca >13 with Symptoms)

Patient with Ca 14, dehydration, altered mental status, AKI
    ↓
EMERGENCY MANAGEMENT:

1. AGGRESSIVE IV HYDRATION (FIRST-LINE)
   ├─ Normal saline 200–500 mL/hr IV
   ├─ Goal: Urine output 200–300 mL/hr
   ├─ Duration: 12–24 hours (rehydrate intravascular space)
   └─ Monitor: Daily weights, JVD, lung sounds (avoid pulmonary edema)
   └─ Mechanism: NS dilutes Ca, increases GFR (Ca filtration), increases Ca excretion
   └─ Efficacy: Reduces Ca by 2–3 mg/dL with good urine output
    ↓
2. CALCITONIN (rapid onset, short-lived)
   ├─ Dose: 4–8 IU/kg SC/IV q6–12h
   ├─ Onset: 2–4 hours (faster than other agents)
   ├─ Duration: 48–72 hours (short; rapid tachyphylaxis develops)
   ├─ Efficacy: Ca reduction ~2–3 mg/dL in most patients
   ├─ Advantage: Safe in renal failure, rapid action
   └─ Use: Bridge therapy while waiting for bisphosphonate/denosumab to work
    ↓
3. BISPHOSPHONATE (slower onset, long-lasting)
   ├─ Zoledronic acid (Zometa): 4 mg IV infusion over 15 min
   │  └─ Onset: 2–3 days; peak effect day 4–5
   │  └─ Duration: 3–4 weeks
   │  └─ Efficacy: 60–80% achieve Ca normalization
   │  └─ Caution: Renal toxicity risk if eGFR <30; contraindicated if Cr >4.5
   ├─ Pamidronate: 60–90 mg IV infusion over 2–4 hours
   │  └─ Older agent; similar efficacy but longer infusion time
   └─ Mechanism: Inhibit osteoclast activity; slow bone resorption
    ↓
4. DENOSUMAB (alternative to bisphosphonate)
   ├─ Dose: 120 mg SC once, may repeat in 7 days
   ├─ Onset: 2–3 days
   ├─ Advantage: No renal dose adjustment needed; effective even if eGFR <30
   ├─ Efficacy: 70–80% achieve normalization
   └─ Cost: Significantly more expensive than zoledronic acid (~$5000 vs. $200)
    ↓
5. LOOP DIURETICS (CONTROVERSIAL)
   └─ OLD teaching: "Force" urine output with furosemide
   └─ MODERN view: NOT recommended routinely
   └─ Rationale: Furosemide ↑ Ca reabsorption in loop; counterproductive
   └─ Use only: Severe fluid overload (pulmonary edema) despite hydration

Chronic Hypercalcemia Management

Monitoring Post-Treatment

• Recheck Ca at 48 hr (bisphosphonate) or 4 hr (denosumab) to assess response
• Monitor Cr closely (HCM causes dehydration + AKI; improved hydration should improve renal function)
• Check phosphate & magnesium (HCM causes hypokalemia & hypomagnesemia; supplement if needed)
• Assess volume status: Daily weights; discontinue hydration once euvolemic