# Hypercalcemia Diagnostic Algorithm > 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. - Skill: `dromlakhani/hypercalcemia-diagnostic-algorithm` (Agent Skill) - Install (CLI): `npx skillmds@latest add dromlakhani/hypercalcemia-diagnostic-algorithm` - Raw SKILL.md: https://api.skillmd.com/api/skills/dromlakhani/hypercalcemia-diagnostic-algorithm/raw - Safety review: pending (external: skill-scanner PASS, skillspector PASS) - Works with: Claude Code, Claude.ai, OpenAI Codex - Category: Coding & Dev Tools - Author: dromlakhani (https://skillmd.com/u/dromlakhani) - Updated: 2026-09-08 - Page: https://skillmd.com/skills/dromlakhani/hypercalcemia-diagnostic-algorithm --- # 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.