What is the approach to assessing hypercalcemia, including definition, differential diagnosis, history, physical examination, investigations, empiric treatment, and indications for referral?

Approach to Assessment of Hypercalcemia

Definition

Hypercalcemia is defined as corrected serum calcium >10.5 mg/dL, with severity classified as mild (10-11 mg/dL), moderate (11-12 mg/dL), or severe (>14 mg/dL). 1, 2, 3

• Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 1, 2
• Alternatively, measure ionized calcium directly (more accurate): mild = 5.6-8.0 mg/dL (1.4-2 mmol/L), severe ≥10 mg/dL (≥2.5 mmol/L) 3, 4

Differential Diagnosis

Primary hyperparathyroidism and malignancy account for 90% of all hypercalcemia cases. 3

PTH-Dependent (Elevated or Normal PTH):

• Primary hyperparathyroidism (most common outpatient cause) 2, 3
• Familial hypocalciuric hypercalcemia (FHH) 5
• Tertiary hyperparathyroidism in chronic kidney disease 6, 7
• Lithium use 4

PTH-Independent (Suppressed PTH <20 pg/mL):

• Malignancy (most common inpatient cause): humoral hypercalcemia via PTHrP (squamous cell, renal cell carcinoma), osteolytic metastases, or hematologic malignancies 2, 7, 3
• Granulomatous diseases (sarcoidosis, tuberculosis) - elevated 1,25-dihydroxyvitamin D 6, 2, 7
• Vitamin D intoxication - elevated 25-hydroxyvitamin D 2, 7
• Medications: thiazide diuretics, calcium/vitamin D supplements, vitamin A 6, 3, 4
• Endocrinopathies: thyrotoxicosis, adrenal insufficiency 3, 4
• Immobilization 3, 4
• Williams syndrome (pediatric) 6

History

Symptom Characterization by Severity:

• Mild hypercalcemia (10-11 mg/dL): Often asymptomatic (80%), but may have fatigue, constipation, polyuria, polydipsia 1, 3
• Moderate hypercalcemia (11-12 mg/dL): Nausea, vomiting, abdominal pain, confusion, myalgia 1, 2, 7
• Severe hypercalcemia (>14 mg/dL): Mental status changes, bradycardia, hypotension, dehydration, acute renal failure, somnolence, coma 1, 2, 3

Red Flags:

• Rapid onset over days to weeks suggests malignancy 3
• Weight loss, night sweats, bone pain suggest malignancy 3
• Kidney stones, bone pain, fractures suggest primary hyperparathyroidism 2
• Extreme irritability, vomiting in infants suggests Williams syndrome 6

Risk Factors to Elicit:

• Cancer history (especially lung, breast, kidney, multiple myeloma) 2, 7
• Medication review: thiazides, lithium, calcium/vitamin D supplements, vitamin A 6, 3, 4
• Chronic kidney disease with calcium-based phosphate binders 6, 7
• Granulomatous disease history (sarcoidosis, TB) 6, 2
• Family history of hypercalcemia or kidney stones (FHH, primary hyperparathyroidism) 5
• Immobilization or prolonged bed rest 3, 4

Physical Examination (Focused)

• Volume status: Assess for dehydration (dry mucous membranes, decreased skin turgor, orthostatic hypotension) 1, 8
• Neurological: Mental status, confusion, lethargy, hyporeflexia 1, 3
• Cardiovascular: Bradycardia, shortened QT interval on ECG, hypertension 1, 2
• Abdominal: Tenderness, constipation 3
• Musculoskeletal: Muscle weakness, bone tenderness 7
• Lymphadenopathy or masses: Suggests malignancy or sarcoidosis 6, 3
• Neck examination: Palpable parathyroid adenoma (rare) 2

Investigations

Initial Laboratory Panel (All Patients):

The first-line test is serum intact PTH, which distinguishes PTH-dependent from PTH-independent causes. 2, 3

• Corrected calcium or ionized calcium 1, 2
• Serum albumin 1, 2
• Intact parathyroid hormone (iPTH) 1, 2, 3
• Serum phosphorus 1, 2
• Magnesium 1, 2
• Blood urea nitrogen and creatinine 1, 2
• Alkaline phosphatase 6
• Electrolytes (chloride for hyperchloremic metabolic acidosis in primary hyperparathyroidism) 2

Second-Line Tests (Based on PTH Result):

If PTH elevated or inappropriately normal:

• 24-hour urine calcium and creatinine to calculate calcium/creatinine clearance ratio 5
  • Ratio ≤0.01 suggests FHH; ratio >0.02 suggests primary hyperparathyroidism 5
• Consider CASR gene testing if ratio ≤0.020 5
• Bone density scan if primary hyperparathyroidism confirmed 2

If PTH suppressed (<20 pg/mL):

• PTH-related protein (PTHrP) - elevated in humoral hypercalcemia of malignancy 1, 2, 7
• 25-hydroxyvitamin D - elevated in vitamin D intoxication 1, 2, 7
• 1,25-dihydroxyvitamin D - elevated in granulomatous diseases, lymphomas 6, 1, 2
• Serum and urine protein electrophoresis if multiple myeloma suspected 2
• Chest X-ray or CT for malignancy or sarcoidosis 6
• TSH if thyrotoxicosis suspected 4

Expected Findings by Etiology:

• Primary hyperparathyroidism: Elevated/normal iPTH, hypophosphatemia, hyperchloremic metabolic acidosis, elevated urine calcium 2
• Malignancy: Suppressed PTH, elevated PTHrP, rapid onset, higher calcium levels 2, 7
• Granulomatous disease: Suppressed PTH, elevated 1,25-dihydroxyvitamin D, normal/low 25-hydroxyvitamin D 6, 2
• Vitamin D intoxication: Suppressed PTH, elevated 25-hydroxyvitamin D 2, 7
• FHH: Normal/elevated PTH, low 24-hour urine calcium, calcium/creatinine clearance ratio ≤0.01 5

Empiric Treatment

Mild Hypercalcemia (10-11 mg/dL, Asymptomatic):

Observation is appropriate for asymptomatic patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease. 3

• Avoid dehydration and prolonged immobilization 8, 3
• Discontinue offending medications (thiazides, calcium/vitamin D supplements) 6, 3
• Treat underlying cause 3

Moderate to Severe Hypercalcemia (≥11 mg/dL or Symptomatic):

Initiate IV normal saline immediately to correct hypovolemia and promote calciuresis, targeting urine output ≥100 mL/hour (3 mL/kg/hour in children <10 kg). 1, 2

1. Hydration (First-line):

   • IV normal saline to restore volume and promote calciuresis 1, 2, 8
   • Loop diuretics (furosemide) only after volume repletion in patients with renal/cardiac insufficiency 2

2. Bisphosphonates (After hydration initiated):

   • Zoledronic acid 4 mg IV over 15 minutes is preferred over pamidronate for moderate to severe hypercalcemia, especially malignancy-associated. 1, 2, 9
   • Onset of action: 2-4 days, peak effect: 4-7 days 8
   • Monitor for renal toxicity and osteonecrosis of jaw with chronic use 1, 2

3. Calcitonin (For immediate short-term effect):

   • Use while waiting for bisphosphonates to take effect in severe symptomatic cases 1, 2
   • Rapid onset (4-6 hours) but modest effect 8

4. Cause-Specific Treatments:

   • Glucocorticoids: Primary treatment for vitamin D-mediated hypercalcemia (sarcoidosis, lymphomas, vitamin D intoxication, granulomatous disorders) 1, 2, 7, 8
   • Denosumab 120 mg subcutaneously: For refractory hypercalcemia, especially with renal impairment where bisphosphonates contraindicated 1, 2
   • Dialysis: Reserved for severe hypercalcemia with kidney failure 2
   • Cinacalcet: For parathyroid carcinoma or severe primary hyperparathyroidism when surgery not feasible 10

5. Pediatric Considerations (Williams Syndrome):

   • Low-calcium diet and increased water intake under medical supervision 6, 1, 7
   • Avoid multivitamins containing vitamin D 6

Indications to Refer

Endocrinology Referral:

• Primary hyperparathyroidism requiring parathyroidectomy evaluation 2
• Persistent hypercalcemia or hypercalciuria 6
• Complex vitamin D metabolism disorders 6

Nephrology Referral:

• Chronic kidney disease with hypercalcemia 6
• Nephrocalcinosis 6
• Renal failure requiring dialysis 2

Surgery Referral (Parathyroidectomy):

Parathyroidectomy is indicated for primary hyperparathyroidism with: symptomatic disease, osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L (>1 mg/dL) above upper normal limit. 2, 3

Oncology Referral:

• Malignancy-associated hypercalcemia requiring cancer-directed therapy 2, 7

Pediatric Subspecialty:

• Williams syndrome with persistent hypercalcemia 6

Critical Pitfalls

1. Failing to correct calcium for albumin or measure ionized calcium directly - hyperalbuminemia can mask true calcium status; total calcium alone is often inaccurate 1, 4

2. Administering loop diuretics before adequate volume repletion - worsens dehydration and hypercalcemia 2

3. Missing familial hypocalciuric hypercalcemia (FHH) - inappropriately pursuing parathyroidectomy when 24-hour urine calcium is low; always calculate calcium/creatinine clearance ratio when PTH is elevated 5

4. Using bisphosphonates in severe renal impairment without dose adjustment - increases risk of renal toxicity; consider denosumab instead 1, 2

5. Restricting calcium intake without medical supervision in normocalcemic patients - can worsen bone health 6

6. Overlooking medication-induced hypercalcemia - failing to discontinue thiazides, calcium/vitamin D supplements, or lithium 6, 3

7. Not recognizing malignancy as the cause in hospitalized patients with rapid-onset hypercalcemia - delays cancer-directed therapy which is essential for long-term control 2, 3

8. Giving vitamin D supplements to patients with granulomatous disease or hypercalcemia - worsens hypercalcemia due to increased 1,25-dihydroxyvitamin D production 6, 1, 7

9. Using NSAIDs or IV contrast in patients with renal impairment and hypercalcemia - worsens renal function 1

10. Treating hypercalcemia without identifying and treating the underlying cause - leads to recurrence; definitive management requires addressing primary disease 1, 3

11. Misinterpreting "normal" PTH in the setting of hypercalcemia - PTH should be suppressed when calcium is elevated; a "normal" PTH is inappropriately elevated and suggests primary hyperparathyroidism 2, 3

12. Delaying bisphosphonate administration - should be given early after starting hydration due to 2-4 day onset of action 8