Hypercalcemia 5 mark answer
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Hypercalcemia
Definition
Hypercalcemia is defined as a total serum calcium above 10.5 mg/dL (2.62 mmol/L) or an ionized serum calcium above 5.25 mg/dL (1.31 mmol/L). Severity is graded as:
- Mild: < 12 mg/dL
- Moderate: 12-14 mg/dL
- Severe: > 14 mg/dL
Prevalence is 1-2% in the general population and 2-5% in hospitalized patients.
Causes (Etiology)
Three fundamental mechanisms drive hypercalcemia: increased bone resorption, increased GI calcium absorption, and decreased renal calcium excretion.
PTH-dependent (elevated PTH):
- Primary hyperparathyroidism - most common outpatient cause; solitary parathyroid adenoma (80%), multiglandular hyperplasia (15%), carcinoma (<1%)
- Tertiary hyperparathyroidism (autonomous PTH secretion in chronic renal failure)
- Familial hypocalciuric hypercalcemia (FHH) - altered calcium-sensing receptor set point
PTH-independent (suppressed PTH):
- Malignancy - most common inpatient cause (accounts for > 90% combined with 1° HPT); mechanisms include:
- PTHrP (PTH-related peptide) secretion - humoral hypercalcemia of malignancy (lung, breast, squamous cell tumors)
- Osteolytic bone metastases (breast, myeloma)
- Ectopic 1,25(OH)₂D production (lymphoma)
- Granulomatous diseases (sarcoidosis, TB) - macrophage conversion of 25-OH-D to active 1,25(OH)₂D
- Vitamin D toxicity / Vitamin A excess
- Drugs: thiazide diuretics, lithium, calcium carbonate (milk-alkali syndrome)
- Endocrine: thyrotoxicosis, Addison disease, pheochromocytoma, acromegaly
- Immobilization (especially with Paget disease or malignancy)
Clinical Features - "Bones, Stones, Moans, and Abdominal Groans"
Symptoms generally appear when calcium exceeds 12 mg/dL and are nearly universal above 14 mg/dL. Onset correlates with rate of rise, not just absolute level.
| System | Features |
|---|---|
| Renal ("Stones") | Nephrolithiasis, nephrocalcinosis, polyuria, polydipsia (nephrogenic DI), renal insufficiency |
| Musculoskeletal ("Bones") | Bone pain, osteopenia/osteoporosis, pathologic fractures, proximal myopathy, weakness |
| GI ("Groans") | Nausea, vomiting, anorexia, constipation, peptic ulcer disease, pancreatitis |
| Neuropsychiatric ("Moans") | Fatigue, lethargy, difficulty concentrating, depression, confusion, stupor, coma (severe) |
| Cardiac | Bradycardia, first-degree AV block, arrhythmias, shortened QT interval on ECG |
Diagnosis
- Confirm hypercalcemia - total serum calcium corrected for albumin: corrected Ca = measured Ca + 0.8 × (4 - albumin g/dL); or measure ionized calcium directly
- PTH level - the pivotal first test:
- Elevated/inappropriately normal PTH → primary hyperparathyroidism
- Suppressed PTH → malignancy (check PTHrP), granulomatous disease (check 1,25-OH-D), drug causes
- Additional workup: serum phosphate (low in HPT; high in bony mets), 24-hour urine calcium, PTHrP, 25-OH-D, 1,25-OH-D, serum protein electrophoresis, imaging (DEXA, parathyroid scintigraphy/US)
Primary HPT: typically mild hypercalcemia (<12 mg/dL), often asymptomatic, chronic
Malignancy: typically severe (>12 mg/dL), acutely symptomatic, obvious primary tumor
Malignancy: typically severe (>12 mg/dL), acutely symptomatic, obvious primary tumor
Treatment
Mild, asymptomatic (Ca < 12 mg/dL): treat underlying cause; monitor
Moderate-to-severe or symptomatic - urgent management:
- IV 0.9% Normal Saline - first and most important step; vigorous hydration (200-500 mL/hr) restores volume, enhances urinary calcium excretion ("saline diuresis")
- Loop diuretics (furosemide) - only after adequate hydration; promotes calciuresis
- Bisphosphonates (zoledronic acid, pamidronate) - IV; inhibit osteoclast-mediated bone resorption; onset 2-4 days, peak effect 4-7 days; drug of choice for hypercalcemia of malignancy
- Calcitonin - rapid but short-lived (tachyphylaxis in 48 hrs); useful for immediate control while awaiting bisphosphonate effect
- Glucocorticoids - particularly effective for granulomatous disease and vitamin D toxicity (inhibit 1,25-OH-D synthesis)
- Denosumab - RANK-L inhibitor; used for bisphosphonate-refractory malignancy-related hypercalcemia
- Dialysis - for severe hypercalcemia with renal failure; most rapid and effective option in this setting
- Cinacalcet (calcimimetic) - for primary HPT not amenable to surgery; lowers PTH by increasing calcium receptor sensitivity
- Parathyroidectomy - definitive treatment for primary HPT meeting surgical criteria
Key points to remember:
- Primary HPT and malignancy together account for >90% of all hypercalcemia cases
- Classic mnemonic: "Bones, Stones, Moans, and Abdominal Groans"
- ECG hallmark: shortened QT interval (Ca stabilizes cardiac membranes)
- PTH is the pivotal diagnostic test - it separates parathyroid from non-parathyroid causes
- Saline hydration is always the first step in acute management
Sources: Goldman-Cecil Medicine, 27e; Textbook of Family Medicine, 9e
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