| name | hypercalcemia-diagnostic-algorithm |
| description | Work up a patient with confirmed hypercalcemia using the PTH-dependent vs. PTH-independent algorithm — order the right second-tier tests (PTHrP, 25(OH)D, 1,25(OH)2D, SPEP/UPEP, urinary calcium/creatinine clearance ratio, TSH) to reach a diagnosis. Trigger when a clinician asks "what's causing this hypercalcemia", "how to work up high calcium", "what tests to order for hypercalcemia", "PTH is normal what next", "differential diagnosis of hypercalcemia", or shares a confirmed hypercalcemia and asks for the workup. |
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.
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.
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.
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
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.
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.
SOURCE
Bilezikian JP, Endotext. Approach to Hypercalcemia. NCBI Bookshelf NBK279129. Section: Hypercalcemic Disorders; Clinical Assessment; Figure 8.
