What are the causes and treatments of concurrent hyponatremia and hypercalcemia?

Concurrent Hyponatremia and Hypercalcemia: Causes and Management

The combination of low sodium and high calcium most commonly indicates hypercalcemia of malignancy, particularly from lung cancer (especially squamous cell), multiple myeloma, or other malignancies that produce both PTHrP-mediated hypercalcemia and SIADH. 1, 2

Primary Causes

Malignancy (Most Common)

• Lung cancer is the leading cause, occurring in 10-25% of patients, with squamous cell histology being most common 1
• Multiple myeloma frequently presents with both hypercalcemia and hyponatremia 1
• The hyponatremia in malignancy typically results from SIADH (affecting 1-5% of lung cancer patients), while hypercalcemia stems from PTHrP production or osteolytic bone lesions 1, 3
• There is a statistically significant association between hyponatremia and neoplastic etiology of hypercalcemia - among patients with hypercalcemia, those with cancer are more likely to have concurrent hyponatremia 2

Other Causes

• Primary hyperparathyroidism with concurrent SIADH from another cause 4
• Granulomatous diseases (sarcoidosis) can cause hypercalcemia through increased calcitriol production, with concurrent SIADH 1, 4
• Medication-induced: thiazide diuretics can cause both hypercalcemia and hyponatremia 4, 3

Diagnostic Approach

Initial Laboratory Evaluation

• Serum calcium (corrected for albumin), ionized calcium, and sodium levels 1, 4
• Intact PTH level - this is the most important initial test: elevated/normal PTH suggests primary hyperparathyroidism; suppressed PTH (<20 pg/mL) indicates PTH-independent causes like malignancy 1, 4
• PTHrP level if PTH is suppressed - elevated in most malignancy-related hypercalcemia 1
• Serum and urine osmolality, urine sodium to evaluate hyponatremia etiology 1, 5

Volume Status Assessment

• Hypercalcemia typically causes polyuria and dehydration through nephrogenic diabetes insipidus 1
• However, concurrent SIADH causes euvolemia or mild hypervolemia 1, 5
• This creates a complex picture requiring careful clinical assessment 5

Additional Testing

• Chest imaging to evaluate for lung malignancy 1
• Serum protein electrophoresis and free light chains if multiple myeloma suspected 1
• 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D if granulomatous disease suspected 1

Treatment Strategy

Hypercalcemia Management (Priority)

Severe hypercalcemia (>14 mg/dL or symptomatic) requires immediate treatment as it is life-threatening 4, 6

• IV crystalloid fluids (normal saline) for rehydration - initial therapy for moderate to severe hypercalcemia 1, 4
• Loop diuretics (furosemide) after volume repletion to enhance calcium excretion 1
• Bisphosphonates (zoledronic acid or pamidronate) - usually effective within 2-4 days 1
• Denosumab preferred in patients with renal impairment 1
• Calcitonin for rapid but temporary effect (1-4 hours) 7
• Glucocorticoids if hypercalcemia is due to granulomatous disease, lymphoma, or vitamin D intoxication 1, 4

Hyponatremia Management (Secondary Priority)

The rate of sodium correction must not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 5

For SIADH (Most Common in Malignancy)

• Fluid restriction to <1 L/day is first-line for mild-moderate asymptomatic SIADH 1, 5
• 3% hypertonic saline for severe symptomatic hyponatremia (<120 mEq/L with neurological symptoms), targeting 6 mmol/L correction over 6 hours 5
• Vasopressin receptor antagonists (tolvaptan, conivaptan) for resistant cases 1, 5

Critical Consideration

• Normal saline used for hypercalcemia treatment may worsen SIADH-related hyponatremia 5
• Monitor sodium levels every 2-4 hours during initial treatment 5
• Balance the need for volume repletion (hypercalcemia) against worsening hyponatremia 5

Treatment of Underlying Cause

• Chemotherapy or radiation for malignancy-related hypercalcemia 1
• Parathyroidectomy for primary hyperparathyroidism if indicated 4
• Discontinue offending medications (thiazides, vitamin D, calcium supplements) 4

Common Pitfalls

• Failing to recognize malignancy as the underlying cause when both electrolyte abnormalities coexist 2
• Overly rapid correction of chronic hyponatremia leading to osmotic demyelination syndrome 5
• Using fluid restriction for hyponatremia before adequately treating severe hypercalcemia - hypercalcemia takes priority as it is immediately life-threatening 4, 6
• Not monitoring sodium levels frequently during aggressive hydration for hypercalcemia 5
• Ignoring the poor prognosis - median survival after discovery of hypercalcemia of malignancy in lung cancer is approximately 1 month 1

Prognosis

• Hypercalcemia of malignancy carries a poor prognosis with median survival of approximately 1 month in lung cancer patients 1
• Asymptomatic primary hyperparathyroidism has excellent prognosis with appropriate management 4
• The presence of both electrolyte abnormalities strongly suggests advanced malignancy requiring urgent oncologic evaluation 2