Approach to Assessment of Hypercalcemia

Definition and Classification

Hypercalcemia is defined as serum calcium >10.5 mg/dL (>2.6 mmol/L) or ionized calcium >5.6 mg/dL (>1.4 mmol/L). 1

Severity Classification:

Mild: Total calcium >10.5 to <12 mg/dL (ionized 5.6-8.0 mg/dL / 1.4-2.0 mmol/L) 1
Moderate: Total calcium 12-14 mg/dL 2
Severe: Total calcium ≥14 mg/dL (≥3.5 mmol/L) or ionized calcium ≥10 mg/dL (≥2.5 mmol/L) 1

Differential Diagnosis

The two most common causes account for 90% of all hypercalcemia cases: 1

Primary hyperparathyroidism (PHPT) - most common in outpatients 3
Malignancy-associated hypercalcemia - most common in inpatients 3

Other Important Causes: 4

Granulomatous diseases (sarcoidosis, tuberculosis) 2
Vitamin D intoxication from excessive supplementation 2
Medications: thiazide diuretics, lithium, calcium/vitamin D supplements 1
Endocrinopathies: thyrotoxicosis 4
Immobilization 4
Familial hypocalciuric hypercalcemia (FHH) 4
Chronic kidney disease with tertiary hyperparathyroidism 2
Williams syndrome (pediatric) 2

History

Key Characteristics to Elicit:

Constitutional Symptoms (present in ~20% of mild cases): 1

Fatigue, weakness, constipation 1
Polyuria and polydipsia 2
Nausea, vomiting, abdominal pain 2
Confusion, somnolence (severe cases) 1

Red Flags:

Severe hypercalcemia (≥14 mg/dL) presenting with: 1

Altered mental status, confusion, or coma 1
Severe dehydration 2
Rapid onset over days to weeks 1
Known malignancy (suggests hypercalcemia of malignancy with median survival ~1 month) 5

Risk Factors:

Malignancy-Related: 6

Squamous cell carcinomas (lung, head/neck) 6
Renal cell carcinoma, ovarian cancer 6
Breast cancer, multiple myeloma 6

Medication/Supplement History: 7

Thiazide diuretics 1
Lithium 4
Calcium supplements (>500 mg/day) 5
Vitamin D supplements (>400 IU/day) 5
Vitamin A 1

Medical Conditions: 2

Chronic kidney disease (especially on calcium-based phosphate binders) 2
Prolonged immobilization 4
Granulomatous disease history 2

Physical Examination (Focused)

Cardiovascular: 5

Bradycardia, hypotension (severe hypercalcemia) 2
ECG changes: shortened QT interval, QT prolongation in severe cases 5

Neurological: 1

Mental status assessment (confusion, somnolence in severe cases) 1
Muscle weakness, hyporeflexia 2

Volume Status: 8

Signs of dehydration (dry mucous membranes, decreased skin turgor, orthostatic hypotension) 8

Malignancy Signs: 5

Lymphadenopathy (lymphoma) 5
Breast masses (breast cancer) 6
Lung findings (lung cancer) 6

Pediatric-Specific (Williams Syndrome): 2

Extreme irritability, vomiting, constipation, muscle cramps 2

Investigations and Expected Findings

First-Line Laboratory Tests:

Essential Initial Workup: 8

Serum calcium (total and ionized) - ionized calcium is more accurate than corrected calcium 4
Albumin - for corrected calcium calculation if ionized unavailable 8
Intact parathyroid hormone (iPTH) - THE MOST IMPORTANT INITIAL TEST 8, 1
Serum creatinine and BUN - assess renal function 8
Serum phosphorus - typically low in PHPT, variable in malignancy 8
Magnesium - assess for deficiency 8

Expected Findings Based on iPTH: 1

Elevated or inappropriately normal PTH (>20 pg/mL): Primary hyperparathyroidism 1
Suppressed PTH (<20 pg/mL): PTH-independent causes (malignancy, vitamin D excess, granulomatous disease) 1

Second-Line Tests (Based on Initial Results):

If PTH Suppressed: 8

PTHrP (parathyroid hormone-related protein) - elevated in humoral hypercalcemia of malignancy 2
25-hydroxyvitamin D and 1,25-dihydroxyvitamin D - measure BOTH together for diagnostic accuracy 8
Malignancy workup if PTHrP elevated 5

If PTH Elevated/Normal: 8

25-hydroxyvitamin D and 1,25-dihydroxyvitamin D 8
24-hour urine calcium - low in familial hypocalciuric hypercalcemia 4

Additional Tests: 8

Serum osmolality - if dehydration suspected (>300 mOsm/kg indicates dehydration) 8
ECG - assess QT interval, arrhythmias 5

Special Population Considerations:

Chronic Kidney Disease: 8

Interpret PTH cautiously as secondary hyperparathyroidism can coexist 8

Pediatric (Williams Syndrome): 8

Monitor calcium every 4-6 months until age 2, then every 2 years 8

Sarcoidosis Suspected: 8

Baseline serum calcium even if asymptomatic (hypercalcemia occurs in ~6% of patients) 8

Empiric Treatment

Mild Hypercalcemia (Asymptomatic):

Observation may be appropriate if: 1

Age >50 years 1
Calcium <1 mg/dL above upper normal limit 1
No skeletal or kidney disease 1

Otherwise, treat underlying cause (parathyroidectomy for PHPT, cancer treatment for malignancy) 1

Moderate to Severe Hypercalcemia:

Immediate Management Algorithm: 5

IV Normal Saline Hydration (FIRST-LINE): 5
- Target urine output 100-150 mL/hour (3 mL/kg/hour in children <10 kg) 5
- Avoid overhydration in cardiac/renal insufficiency 5
- Add loop diuretics (furosemide) ONLY after volume repletion if needed to prevent fluid overload 5
IV Bisphosphonates (CORNERSTONE THERAPY): 5
- Zoledronic acid 4 mg IV over ≥15 minutes (PREFERRED) 5, 6
- Alternative: Pamidronate IV if zoledronic acid unavailable 5
- Onset of action: 2-4 days 6
- Check serum creatinine before each dose; withhold if renal deterioration 5
- Adjust dose for renal impairment 5
Calcitonin (Bridge Therapy): 5
- Dose: 100 IU subcutaneously or intramuscularly every 12 hours, OR 200 IU/day nasal spray 5
- Rapid onset (within hours) but limited efficacy 5
- Use as bridge until bisphosphonates take effect 5

Cause-Specific Treatment:

Vitamin D-Mediated Hypercalcemia (Sarcoidosis, Lymphoma, Vitamin D Intoxication): 5

Glucocorticoids (PRIMARY TREATMENT): Prednisone 1 mg/kg/day PO or methylprednisolone IV equivalent 5
Taper over 2-4 months depending on response 5
Add PPI for GI prophylaxis 5
Add pneumocystis prophylaxis if ≥20 mg methylprednisolone equivalent for ≥4 weeks 5
Screen for tuberculosis before initiating in granulomatous disease 5

Multiple Myeloma: 5

Hydration + zoledronic acid 4 mg IV + glucocorticoids ± calcitonin 5
Continue bisphosphonates up to 2 years 5
Consider plasmapheresis for symptomatic hyperviscosity 5

Severe Hypercalcemia with Renal Failure: 5

Hemodialysis with calcium-free or low-calcium dialysate 5

Primary Hyperparathyroidism: 2

Parathyroidectomy indicated for: symptomatic patients, osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L above upper limit 2

Chronic Kidney Disease: 5

Restrict calcium-based phosphate binders 5
Avoid routine calcitriol/vitamin D analogues in non-dialysis CKD 5
Consider parathyroidectomy for tertiary hyperparathyroidism refractory to medical therapy 5

Supportive Measures:

Correct Hypocalcemia Post-Treatment: 5

Oral calcium 500 mg + vitamin D 400 IU daily during bisphosphonate treatment 5
Treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 5

Discontinue Offending Agents: 5

Stop vitamin D supplements 5
Stop calcium supplements 5
Discontinue nephrotoxic medications 5

Indications to Refer

Endocrinology Referral:

Immediate/Urgent: 8

Severe hypercalcemia (≥14 mg/dL) 1
Symptomatic hypercalcemia with confusion, altered mental status 1
Suspected parathyroid carcinoma 9
Persistent hypercalcemia despite adequate hydration 8

Routine: 8

Primary hyperparathyroidism requiring surgical evaluation 2
Unclear etiology after initial workup 8
Chronic kidney disease with tertiary hyperparathyroidism 5

Oncology Referral:

Urgent: 5

Suspected malignancy-associated hypercalcemia (PTH suppressed, PTHrP elevated) 2
Known malignancy with new hypercalcemia 5

Nephrology Referral:

Urgent: 5

Severe hypercalcemia with acute renal failure requiring dialysis 5
CKD with refractory hypercalcemia 5

Surgery Referral:

Routine: 2

Primary hyperparathyroidism meeting surgical criteria 2
Parathyroid carcinoma 9

Critical Pitfalls

Diagnostic Pitfalls:

Relying on corrected calcium instead of ionized calcium - corrected calcium is often inaccurate; ionized calcium is the gold standard 4
Pseudo-hypercalcemia - elevated calcium in test tube from hemolysis or improper sampling; repeat with arterial sample if suspected 7
Misinterpreting PTH in CKD patients - secondary hyperparathyroidism can coexist with other causes of hypercalcemia 8
Failing to measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together - their relationship provides critical diagnostic information 8
Missing familial hypocalciuric hypercalcemia (FHH) - check 24-hour urine calcium; FHH has low urinary calcium and does NOT require treatment 4

Treatment Pitfalls:

Using loop diuretics before adequate volume repletion - worsens dehydration and hypercalcemia 5
Delaying bisphosphonate therapy - bisphosphonates take 2-4 days to work; start early, use calcitonin as bridge 5
Using bisphosphonates without checking renal function - can worsen kidney injury; adjust dose for CrCl <60 mL/min 5
Failing to correct hypocalcemia before bisphosphonate therapy - increases risk of severe hypocalcemia, especially with denosumab 5
Using NSAIDs or IV contrast in patients with renal impairment - worsens kidney function 5
Restricting calcium intake excessively without supervision - can worsen bone disease, especially in CKD 5
Continuing nephrotoxic medications - discontinue all nephrotoxic agents in hypercalcemic patients 5
Treating asymptomatic hypocalcemia post-treatment - only treat symptomatic hypocalcemia (tetany, seizures) 5
Missing malignancy-associated hypercalcemia prognosis - median survival ~1 month; have goals-of-care discussion early 5
Forgetting to hold myeloma therapy (lenalidomide/bortezomib) until calcium normalizes - hypercalcemia indicates active disease requiring reassessment 5
Not screening for tuberculosis before starting steroids for granulomatous disease - can reactivate latent TB 5
Restricting calcium in Williams syndrome with normocalcemia - inappropriate and can harm bone health 5

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