Hypercalcemia — Diagnostic Algorithm

Use this skill once hypercalcemia is confirmed (corrected or ionized Ca elevated on ≥2 occasions). The pivot is PTH — it splits the differential cleanly.

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STEP 1 — Order the first-tier panel

For every hypercalcemic patient, order on day one:

• Corrected total calcium + ionized calcium
• Intact PTH (2-site assay — current standard)
• 25(OH)D and 1,25(OH)2D
• Phosphate, magnesium
• Creatinine + eGFR
• 24-h urine calcium and creatinine (calculate Ca/Cr clearance ratio)
• Albumin
• CBC, ALP, LFTs

Then proceed to Step 2 based on PTH.

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STEP 2 — Pivot on PTH

Branch A: PTH is HIGH or INAPPROPRIATELY NORMAL → PTH-dependent

A normal PTH in the setting of hypercalcemia is not normal — PTH should be suppressed. Treat as elevated.

Order:

• 24-h urinary Ca/Cr clearance ratio
  • Formula: (Urine Ca × Serum Cr) / (Serum Ca × Urine Cr)
  • <0.01 → suspect FHH — do not operate; consider CaSR genetics, family screening
  • >0.02 → consistent with PHPT
• Medication review — lithium, thiazides, teriparatide can mimic PHPT
• Family history — MEN1 (parathyroid + pituitary + pancreas), MEN2A (parathyroid + medullary thyroid + pheo), MEN4, HPT-JT (jaw tumour + renal cysts)

Likely diagnoses:

• Sporadic primary hyperparathyroidism (most common, 85–90% single adenoma)
• Familial PHPT / MEN1, 2A, 4 / HPT-JT if family history positive
• Familial Hypocalciuric Hypercalcemia (FHH) if Ca/Cr clearance <0.01
• Tertiary hyperparathyroidism (CKD, post-renal-transplant)
• Lithium- or thiazide-induced
• Ectopic PTH secretion (rare — ovarian, lung, thyroid, thymus, gastric)

Confirm PHPT: two elevated corrected (or ionized) Ca + non-suppressed PTH at least 2 weeks apart.

If diagnosis = PHPT and surgery planned: pre-op imaging (MIBI ± ultrasound), DXA (lumbar spine, hip, distal 1/3 radius), VFA / vertebral X-ray, baseline 24-h urine Ca, eGFR.

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Branch B: PTH is LOW / SUPPRESSED → PTH-independent

The differential is malignancy, vitamin D excess, granulomatous disease, endocrine disorders, or medication.

Order on top of the first-tier panel:

• PTHrP (drives MAH workup)
• SPEP + UPEP + serum free light chains (rule out myeloma)
• TSH (hyperthyroidism)
• Cortisol / ACTH stimulation if hypoadrenalism suspected
• Vitamin A level if dermatologic / neoplastic retinoid use
• Chest X-ray ± CT chest (sarcoid, granulomatous disease, lung cancer)
• Skeletal imaging (X-ray skeletal survey, bone scan, or CT/MRI as guided)
• Medication / supplement history including OTC

Then sub-classify:

B1. PTHrP elevated → Malignancy-Associated Hypercalcemia (MAH)

• Squamous cell tumours (lung, head & neck, oesophagus, cervix, vulva, skin)
• Renal cell, bladder, ovarian carcinoma
• Breast cancer with bone mets
• ATL (HTLV-1), non-Hodgkin lymphoma
• Hypercalcemia is usually a late, advanced-stage finding → search the obvious primary first.

B2. 1,25(OH)2D elevated → Vitamin D activation excess

• Granulomatous disease — sarcoidosis, TB, fungal (histoplasmosis, coccidiomycosis, cryptococcosis), berylliosis, GPA, Crohn's, eosinophilic granuloma, Langerhans cell histiocytosis, cat-scratch
• Lymphoma (Hodgkin, NHL) — extrarenal 1α-hydroxylase
• CYP24A1 inactivating mutation (idiopathic infantile hypercalcemia in adults)

B3. 25(OH)D very high → Vitamin D toxicity

• Excess vitamin D / D2 / D3 / calcitriol intake.

B4. SPEP/UPEP positive → Multiple myeloma

• ~30% of myeloma patients develop hypercalcemia (usually with renal failure / Bence-Jones nephropathy).
• Confirm with bone marrow biopsy; mm-diagnostic-workup skill.

B5. PTHrP, 1,25(OH)2D, SPEP all normal → consider:

• Hyperthyroidism (TSH suppressed)
• Adrenal insufficiency
• Pheochromocytoma, VIPoma, acromegaly (rare)
• Medication — see the medication-induced-hypercalcemia-screener skill
• Immobilisation, rhabdomyolysis (polyuric phase), milk-alkali
• Vitamin A excess

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STEP 3 — Document & act

Once diagnosis is established:

• Confirm with at least two values 2 weeks apart for chronic disorders (PHPT, FHH).
• Treat the underlying cause; if Ca > 12 with symptoms or > 14 in any case → use the acute-hypercalcemia-management skill.
• For PHPT, evaluate end-organ involvement (DXA, VFA, renal imaging, eGFR, 24-h urine Ca) before surgery.

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CLINICAL GUARDRAILS

• A "normal" PTH in a hypercalcemic patient is inappropriate. Treat as PTH-dependent.
• Always check the urinary Ca/Cr clearance ratio in PTH-dependent hypercalcemia before referring for parathyroidectomy — FHH is operatively futile and surgery is harmful.
• Lithium and thiazides can cause a PTH-dependent picture that mimics PHPT — review meds before booking surgery. The hypercalcemia is reversible on stopping the drug.
• Hypercalcemia in malignancy is almost always late-stage. The cancer is rarely occult — look hard, but expect to find it.
• Multiple myeloma is missed if SPEP alone is ordered. Always pair with UPEP and serum free light chains.
• Granulomatous hypercalcemia is sun-/season-dependent — patients with sarcoid often get hypercalcemic in summer or after a small dose of vitamin D supplement.
• Bone scan can be falsely negative in myeloma — use whole-body low-dose CT or PET-CT.

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SOURCE

Bilezikian JP, Endotext. Approach to Hypercalcemia. NCBI Bookshelf NBK279129. Section: Hypercalcemic Disorders; Clinical Assessment; Figure 8.