Hypercalcemia Workup

Step 1 - Confirm True Hypercalcemia

• Serum total calcium > 10.5 mg/dL (2.6 mmol/L), or ionized calcium > 5.3 mg/dL (1.3 mmol/L)
• Rule out false hypercalcemia due to: tourniquet not released during phlebotomy, prolonged venous stasis, hemolysis, or lab error
• Correct for albumin: corrected Ca = measured Ca + 0.8 × (4.0 - serum albumin). Alternatively, measure ionized calcium directly - this bypasses albumin entirely
• Obtain repeat measurements (serum Ca + albumin, at least twice, non-fasting) - this is cost-effective and important before extensive workup

Harrison's Principles of Internal Medicine 22E (2025): "Hyperparathyroidism and cancer account for 90% of all cases."

Step 2 - Clinical History and Chronicity

Step 3 - Initial Laboratory Panel

Step 4 - PTH-Directed Algorithm

PTH Elevated or Normal-High (Inappropriately Unsuppressed)

• Check 24-hour urine calcium:
  • High urine Ca > 4 mg/kg/24 hr (> 0.1 mmol/kg/24 hr): Primary HPT, tertiary HPT, MEN 1, HPT-JT syndrome, lithium use, familial isolated HPT (FIHP)
  • Low urine Ca < 1.5 mg/kg/24 hr (< 0.04 mmol/kg/24 hr): Familial Hypocalciuric Hypercalcemia (FHH) - confirm with family history and genetic testing (CASR mutation)
• Consider MEN syndromes (check for pituitary tumors, pancreatic NETs in MEN1; pheochromocytoma in MEN2A)

PTH Low (< 15 pg/mL) - PTH Suppressed

• PTHrP elevated: Humoral hypercalcemia of malignancy (HHM) - most often squamous cell carcinomas (lung, head/neck, esophagus), renal, bladder
• PTHrP low/normal: Proceed to vitamin D metabolites

Step 5 - Cause-Specific Additional Tests

• Chest X-ray + CT chest/abdomen/pelvis
• Bone scan (note: may be negative in multiple myeloma)
• SPEP/UPEP + serum free light chains (myeloma)
• PSA, mammography as appropriate
• PTHrP assay

• Localization studies (only if parathyroid surgery planned): Sestamibi parathyroid scan, neck ultrasound, 4D CT
• DEXA bone density (T-score at lumbar spine, hip, distal 1/3 radius)
• 24-hour urine calcium and creatinine
• Serum creatinine, renal ultrasound (nephrolithiasis screening)
• 25-OHD level (vitamin D deficiency common in PHPT)
• Consider 24-hour urine for kidney stone risk panel if nephrolithiasis present
• Genetic testing for MEN1/2, HRPT2, CASR if young patient or family history

• Calcium:creatinine clearance ratio (CCCR) = (urine Ca/serum Ca) ÷ (urine Cr/serum Cr)
  • CCCR < 0.01 strongly suggests FHH
  • CCCR > 0.02 supports PHPT
• Family history screening
• CASR, AP2S1, GNA11 genetic panel

• 1,25-OHD2 (elevated due to extrarenal 1-alpha hydroxylase)
• ACE level, chest CT (sarcoidosis)
• BAL or tissue biopsy if needed

Causes Summary (Table)

Quick Reference: PTH Interpretation

PTH is elevated in > 90% of parathyroid-related hypercalcemia and undetectable or low in malignancy-related, vitamin D-related, and high-bone-turnover causes. Measurement of PTH is cost-effective in virtually all hypercalcemic patients. - Harrison's Principles of Internal Medicine 22E, 2025

Hypercalcemia Workup

Step 1 - Confirm True Hypercalcemia

• Repeat the measurement - obtain serum calcium + albumin at least twice (non-fasting); this is cost-effective since hypercalcemia is typically chronic
• Correct for albumin: Corrected Ca = measured Ca + 0.8 × (4.0 - serum albumin g/dL)
• Measure ionized calcium directly if albumin correction is unreliable (paraproteinemia, critical illness) - Rosen's Emergency Medicine recommends ionized Ca over total Ca in hypercalcemic patients
• Rule out false hypercalcemia: tourniquet not released during phlebotomy (hemoconcentration), hemolysis, lab error

Step 2 - Severity Classification

Step 3 - History and Clinical Context (Most Important Filter)

Step 4 - Initial Laboratory Panel

Step 5 - PTH-Directed Algorithm

PTH Elevated or Normal-Unsuppressed

• Primary hyperparathyroidism (PHPT) - adenoma 80%, hyperplasia 15%, carcinoma < 1%
• Tertiary hyperparathyroidism
• Lithium therapy
• MEN 1 or MEN 2A
• HPT-JT syndrome, Familial isolated HPT (FIHP)

• Familial Hypocalciuric Hypercalcemia (FHH) - CASR inactivating mutation
• Neonatal severe hyperparathyroidism (NSHPT)
• Some malignancies

CCCR = (urine Ca / serum Ca) ÷ (urine Cr / serum Cr)

• CCCR < 0.01 = strongly favors FHH
• CCCR > 0.02 = favors PHPT

PTH Low (< 15 pg/mL) - Suppressed

• PTHrP elevated: Humoral Hypercalcemia of Malignancy (HHM) - accounts for ~80% of malignancy-related hypercalcemia; classic tumors: squamous cell (lung, head/neck, esophagus, cervix), renal cell, bladder, ovarian
• PTHrP low/normal: check vitamin D metabolites

Step 6 - Cause-Specific Follow-Up Tests

• Localization (only if surgery planned): Sestamibi parathyroid scan ± neck ultrasound ± 4D CT
• DEXA bone densitometry (lumbar spine, hip, distal 1/3 radius - the latter most sensitive for cortical loss in PHPT)
• 24-hour urine calcium/creatinine + stone risk panel if nephrolithiasis
• 25-OHD level (vitamin D deficiency is common and must be repleted carefully)
• Serum creatinine + renal imaging (nephrolithiasis, nephrocalcinosis)
• Genetic testing if age < 40, multiglandular disease, family history, or jaw tumor: MEN1, CDC73 (HRPT2), CASR, AP2S1

• PTHrP assay
• SPEP/UPEP + serum free light chains (multiple myeloma - note bone scan may be negative)
• CT chest/abdomen/pelvis
• Chest X-ray
• Bone scan (lytic mets)
• PSA, mammography as clinically indicated
• 1,25-OHD2 (lymphoma)

• 1,25-OHD2 (elevated due to extrarenal 1α-hydroxylase in macrophages)
• ACE level, chest CT (sarcoidosis)
• Tissue biopsy or BAL if needed

• CCCR calculation
• Family history screening (autosomal dominant; calcium often mildly elevated in relatives)
• Genetic panel: CASR, AP2S1, GNA11

Summary: Causes by PTH Status

ECG Pearl

• Harrison's Principles of Internal Medicine 22E (2025, McGraw Hill)
• Brenner and Rector's The Kidney, 2-Volume Set
• Rosen's Emergency Medicine: Concepts and Clinical Practice
• Textbook of Family Medicine 9e
• 2025 Practice Guideline: Bouillet B et al., "Primary Hyperparathyroidism: diagnosis," Ann Endocrinol (Paris) [PMID: 39818287]

Hypercalcemia Treatment

Severity Thresholds

Acute Management - Step-by-Step Order

1. IV Normal Saline (First and Always)

• Mechanism: expands ECF, increases GFR, reduces proximal tubular Na⁺ and Ca²⁺ reabsorption, promotes calciuresis
• Most patients are volume-depleted at presentation from hypercalcemia-induced polyuria and natriuresis
• Dose: 200-500 mL/hr based on cardiovascular status; maintain urine output 100-150 mL/hr
• Expected effect: serum Ca falls ~1-3 mg/dL within 24 h
• Monitor closely for volume overload, especially in cardiac/renal impairment
• Onset: hours; Duration: only during infusion

2. Loop Diuretics (after euvolemia is restored)

• Mechanism: block NKCC2 in the thick ascending limb, disrupting the electrochemical gradient for passive paracellular Ca²⁺ reabsorption
• Furosemide 20-40 mg IV; dose adjusted for renal function
• Critical: must be given only after adequate volume resuscitation - loop diuretics before hydration will worsen hypercalcemia by causing further dehydration
• Replete K⁺ and Mg²⁺ aggressively
• Combined saline + furosemide can increase urine Ca excretion to ≥ 500 mg/day

3. IV Bisphosphonates (backbone of antiresorptive therapy)

• Clinical response seen in 2-4 days; Ca nadir reached in 4-7 days
• Can repeat pamidronate after 7 days if hypercalcemia recurs
• Hydrate before infusing - rapid infusion without hydration risks acute kidney injury
• Renal insufficiency is a relative contraindication; dose-adjust or avoid
• Adverse effects: fever (~20%), hypophosphatemia, hypocalcemia, hypomagnesemia; rarely osteonecrosis of the jaw

4. Calcitonin (adjunct for rapid bridging)

• Mechanism: inhibits osteoclast-mediated bone resorption AND increases renal calcium excretion
• Dose: Salmon calcitonin 4-8 IU/kg IM or SC every 6-12 hours
• Lowers Ca by 1-2 mg/dL within hours in 60-70% of patients
• Key limitation: rapid tachyphylaxis - effect lost after 1-2 days; use as bridge while waiting for bisphosphonates to kick in
• Advantages: safe in renal failure, may have analgesic effect in bone mets, no serious toxicity
• Onset: hours; Duration: 1-2 days only

5. Denosumab (for refractory or bisphosphonate-ineligible patients)

• Mechanism: RANKL inhibitor - blocks osteoclast differentiation and function (most potent antiresorptive)
• Dose: 120 mg SC every 4 weeks (some protocols: weekly × 4 weeks then monthly for malignancy)
• Indications: hypercalcemia refractory to bisphosphonates; CKD where bisphosphonates are contraindicated
• Adverse effects: severe hypocalcemia (especially in CKD), jaw osteonecrosis, skin infections
• Monitor calcium closely after administration

6. Glucocorticoids (specific indications)

• Mechanism: inhibit extrarenal 1α-hydroxylase (which converts 25-OHD to 1,25-OHD2 in macrophages), and direct antitumor effect in hematologic malignancies
• Dose: Prednisone 20-60 mg/day PO; taper to minimum effective dose once Ca stabilizes
• Effective specifically in:
  • Granulomatous disease (sarcoidosis, TB, fungal)
  • Vitamin D intoxication
  • Hematologic malignancies (myeloma, lymphoma)
• Not effective for PHPT or solid-tumor humoral hypercalcemia

7. Dialysis (last resort)

• Indications: severe hypercalcemia (Ca > 16 mg/dL) with concurrent CHF or renal insufficiency where aggressive saline loading is not feasible
• Hemodialysis or peritoneal dialysis with low-calcium dialysate
• Onset: hours; can immediately reverse life-threatening hypercalcemia
• Reserved for extreme or special circumstances

Summary Table (Harrison's 22E, Table 422-4)

Cause-Specific Chronic Management

Primary Hyperparathyroidism (PHPT)

1. Corrected serum Ca > 1.0 mg/dL above the upper limit of normal
2. Creatinine clearance < 60 mL/min
3. Age < 50 years
4. T-score ≤ -2.5 at lumbar spine, total hip, femoral neck, or distal 1/3 radius on DXA, or prior fragility fracture
5. 24-hour urine Ca > 400 mg/day with elevated stone risk
6. Imaging-confirmed nephrolithiasis or nephrocalcinosis
7. Patient preference (does not meet criteria but declines surveillance)

• Liberal oral hydration + high-salt diet
• Daily physical activity (reduces bone resorption from immobility)
• Avoid thiazide diuretics and prolonged immobilization
• Cinacalcet (calcimimetic): allosteric activator of CaSR that mimics high Ca, suppressing PTH secretion
  • Dose: 30 mg BID titrated up to 90 mg BID; give with food to reduce nausea
  • Reduces PTH and serum Ca; does not improve bone density
• Oral bisphosphonates (alendronate): improves bone density but minimal effect on Ca levels
• Estrogen/raloxifene in postmenopausal women: modest bone-protective effect

Malignancy-Associated Hypercalcemia

• IV bisphosphonates (zoledronate preferred) + denosumab for refractory cases
• Glucocorticoids + Ca-restricted diet (< 400 mg/day) for lymphoma/myeloma
• These measures rarely give long-term control unless the malignancy itself responds to treatment
• Median survival after malignancy-associated hypercalcemia is < 2 months (reflects advanced disease)

Granulomatous Disease / Vitamin D Toxicity

• Glucocorticoids are first-line alongside saline diuresis
• Dietary calcium restriction is beneficial (unlike malignancy, pathogenesis is intestinal hyperabsorption)
• Avoid sunlight exposure (reduces endogenous Vit D production) in active granulomatous disease
• Hydroxychloroquine is an alternative for steroid-sparing in sarcoidosis

FHH

• No treatment needed - benign, parathyroidectomy does not cure it
• Avoid unnecessary parathyroid surgery

• Harrison's Principles of Internal Medicine 22E (2025) - Table 422-4
• Washington Manual of Medical Therapeutics
• NKF Primer on Kidney Diseases 8e
• Rosen's Emergency Medicine
• Brenner and Rector's The Kidney