Hypercalcemia

Risk factors

• Primary hyperparathyroidism (postmenopausal women, lithium, MEN1/MEN2A)
• Malignancy: squamous cell (lung, head/neck), renal cell, breast — PTHrP; multiple myeloma, breast bone mets — osteolytic; lymphoma, granulomatous disease — calcitriol
• Granulomatous disease — sarcoidosis, TB, histoplasmosis, berylliosis (macrophage 1-alpha-hydroxylase)
• Vitamin D toxicity (high-dose supplements)
• Vitamin A toxicity (retinoid therapy)
• Drugs: thiazides, lithium, teriparatide overdose
• Immobilization (especially with high bone turnover — adolescents, Paget disease)
• Hyperthyroidism, adrenal insufficiency, pheochromocytoma
• Milk-alkali syndrome (chronic high calcium carbonate ingestion)
• Familial hypocalciuric hypercalcemia (FHH) — mild, lifelong, AD, do NOT operate

Pathophysiology

Hypercalcemia arises from increased bone resorption (PTH, PTHrP, lytic metastases, hyperthyroidism), increased intestinal absorption (vitamin D toxicity, calcitriol from granulomas/lymphoma, milk-alkali), or decreased renal excretion (thiazides, FHH). High calcium produces nephrogenic DI (concentrating defect), volume depletion, and AKI, which further raises calcium — vicious cycle.

Clinical presentation

Differential diagnosis

• Primary hyperparathyroidism — PTH elevated/inappropriately normal; hypophosphatemia; chronic
• Humoral hypercalcemia of malignancy (PTHrP) — PTH suppressed; PTHrP elevated; squamous cell lung, head/neck, renal, breast; rapid progression
• Osteolytic metastases / multiple myeloma — Skeletal pain, lytic lesions; suppressed PTH; SPEP/UPEP for myeloma
• Lymphoma / granulomatous (sarcoid, TB) hypercalcemia — Elevated 1,25-OH vitamin D from macrophage activity; suppressed PTH; treat with steroids
• Vitamin D toxicity — Supplement history; elevated 25-OH vitamin D; suppressed PTH
• Familial hypocalciuric hypercalcemia (FHH) — Mild lifelong; LOW 24-h urinary Ca (Ca/Cr clearance ratio <0.01); inactivating CaSR mutation
• Milk-alkali syndrome — Calcium carbonate ingestion; metabolic alkalosis, AKI, suppressed PTH
• Thiazide / lithium induced — Drug history; stop the drug if safe and recheck Ca and PTH in about 3 months before any 24-h urine Ca (thiazides lower urine Ca and can mimic FHH)
• Hyperthyroidism — Mild Ca elevation; symptoms of thyrotoxicosis; suppressed TSH
• Adrenal insufficiency — Mild Ca elevation; orthostatic, low Na, high K

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A["Hypercalcemia confirmed<br/>(corrected Ca or ionized Ca)"] --> B[Measure PTH]
  B --> C{PTH elevated /<br/>inappropriately normal?}
  C -->|Yes| D["24-h urine Ca/Cr ratio<br/>(off thiazides and lithium)"]
  D --> E{"Ratio <0.01?"}
  E -->|Yes| F[FHH — observe; do not operate]
  E -->|No| G[Primary HPT — parathyroidectomy if indicated]
  C -->|"No (suppressed)"| H["Measure PTHrP, 25-OH and 1,25-OH vitamin D, SPEP, TSH"]
  H --> I{PTHrP elevated?}
  I -->|Yes| J["Humoral hypercalcemia of malignancy<br/>(SCC, renal, breast)"]
  I -->|No| K{1,25-OH vitamin D elevated?}
  K -->|Yes| L[Granulomatous disease or lymphoma<br/>→ glucocorticoid]
  K -->|No| M{25-OH vitamin D elevated?}
  M -->|Yes| N[Vitamin D toxicity]
  M -->|No| O[Myeloma / bone mets / drugs<br/>thyrotoxicosis / Addison / milk-alkali]
  A --> P["ACUTE severe: NS hydration<br/>+ calcitonin (bridge)<br/>+ zoledronic acid 4 mg IV or denosumab<br/>± glucocorticoid<br/>± hemodialysis"]

Complications

• Hypercalcemic crisis: severe AKI, coma, arrhythmia
• Nephrolithiasis, nephrocalcinosis, CKD
• Pathologic fracture, osteoporosis
• Pancreatitis, peptic ulcer
• Cardiac arrhythmia, AV block, digoxin toxicity
• Bisphosphonate-related: osteonecrosis of jaw, atypical femoral fracture, acute renal toxicity, post-infusion flu-like reaction
• Denosumab: severe rebound hypercalcemia on discontinuation

PANCE pearls

• Outpatient hypercalcemia = primary HPT until proven otherwise. Inpatient hypercalcemia = malignancy.
• PTH is the single most useful test — high/normal points to parathyroid; suppressed points to non-parathyroid (malignancy, vitamin D toxicity, granuloma).
• Saline hydration is the FIRST step in severe hypercalcemia — most patients are profoundly volume depleted.
• Calcitonin works fast (hours) but tachyphylaxes within 48 h; bisphosphonates are the durable treatment (peak day 4-7).
• Glucocorticoids drop calcium in granulomatous, lymphoma, and vitamin D-toxicity hypercalcemia by inhibiting 1-alpha-hydroxylase.
• Always check 24-h urinary calcium (off thiazides) before parathyroidectomy to exclude FHH (low Ca/Cr ratio = do not operate).
• Patients on digoxin are exquisitely sensitive to hypercalcemia — risk of digoxin toxicity.

References

• Fifth International Workshop on PHPT 2022 — Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop (Bilezikian et al., J Bone Miner Res 2022)
• NEJM Review — Hypercalcemia Associated with Cancer (Stewart, N Engl J Med 2005)
• Endocrine Society 2023 — Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline (El-Hajj Fuleihan et al., J Clin Endocrinol Metab 2023)