EndocrinologyTier 1Disease (DEADMAN)

Hypercalcaemia

Description

  • Corrected Ca >2.60 mmol/L. Ionised calcium is the physiologically active fraction
    • Correction: `measured Ca + 0.02 x (40 - albumin g/L)`
    • Correction formulae fail in critical illness, myeloma and acid-base disturbance - measure ionised calcium
  • Mild <3.0 | Moderate 3.0-3.5 | Severe >3.5 (medical emergency regardless of symptoms)
Clinical - "bones, stones, abdominal groans, psychic moans"
  • Neuromuscular - weakness, fatigue, hyporeflexia
  • GI - anorexia, nausea, vomiting, constipation, abdominal pain, pancreatitis, peptic ulcer
  • Renal - polyuria and polydipsia (nephrogenic DI), stones, nephrocalcinosis, AKI, distal RTA
  • Neuropsychiatric - poor concentration, depression, confusion, coma
  • Cardiac - short QT, bradycardia, heart block, digoxin sensitivity
  • Skeletal - bone pain, fracture, osteitis fibrosa cystica
  • Symptoms depend on rate of rise as much as level - a chronic 3.0 may be asymptomatic, an acute 3.0 will not be

Epidemiology1 exam ›

  • Primary hyperparathyroidism and malignancy account for ~90%
    • Primary HPT dominates in the community and outpatients; malignancy dominates in hospital inpatients
  • Primary hyperparathyroidism: prevalence ~1-3/1000, F>M 3:1, peak post-menopausal
  • Hypercalcaemia of malignancy: 20-30% of cancer patients at some point
  • Familial hypocalciuric hypercalcaemia ~1:78,000

Aetiopathogenesis3 exam ›

Divide by PTH first - it is the only branch point that matters

### A. PTH raised or inappropriately normal ("non-suppressed")

  • Primary hyperparathyroidism - single adenoma ~85%, hyperplasia ~10-15%, carcinoma <1%
  • Tertiary hyperparathyroidism - autonomous gland after long-standing CKD
  • Familial hypocalciuric hypercalcaemia (FHH) - autosomal dominant, inactivating CASR mutation
    • Set-point of the calcium-sensing receptor is reset upward in both parathyroid and kidney
  • Lithium - raises the PTH set-point + inc renal calcium reabsorption (biochemically indistinguishable from FHH)

### B. PTH suppressed

  • Malignancy - four mechanisms
    • PTHrP (humoral hypercalcaemia of malignancy) - the dominant one: squamous (lung, oesophagus, head and neck), renal, bladder, breast
      • PTHrP acts on the PTH receptor -> inc renal Ca reabsorption, inc phosphaturia, inc osteoblast RANKL. Unlike PTH it does not raise 1,25(OH)2D - so calcitriol is low
    • Local osteolysis (~20%) - extensive bone metastases, myeloma, breast
    • Extrarenal calcitriol (~1%) - Hodgkin and non-Hodgkin lymphoma
    • Ectopic PTH - genuinely rare
  • Granulomatous disease - sarcoidosis, TB, silicosis, berylliosis, fungal infection
    • Macrophage 1-alpha-hydroxylase is unregulated by PTH or phosphate
    • Same enzyme is active in placenta and monocytes
  • Vitamin D or A intoxication
  • Drugs - thiazides (inc distal reabsorption), milk-alkali/calcium-alkali syndrome, teriparatide, excess calcium supplementation
  • Endocrine - thyrotoxicosis (inc bone turnover), adrenal insufficiency, phaeochromocytoma, VIPoma, acromegaly
  • Immobilisation (young, high-turnover, Paget disease), rhabdomyolysis recovery phase, TPN

Diagnosis1 exam ›

First-line panel
  • Corrected/ionised calcium, PTH, phosphate, magnesium, UEC, albumin, ALP
  • 25-OH vitamin D; add 1,25(OH)2D if granulomatous or lymphoma suspected
  • PTHrP if PTH suppressed and no obvious malignancy
Pattern recognition
PTHPhosphate1,25(OH)2DUrine Ca
Primary HPTinc / non-suppresseddecincinc
FHHinc / normalNormalNormal*Very low*
PTHrP malignancydecdecdec/normalinc
Osteolytic/myelomadecNormal/incdecinc
Granuloma/lymphomadecinc/normalincinc
Vitamin D excessdecinc/normalNormal (25-OH very high)inc
  • *Calcium:creatinine clearance ratio separates primary HPT from FHH*
    • <0.01 -> FHH (do not operate); >0.02 -> primary HPT
    • Formula: `(urine Ca x serum Cr) / (serum Ca x urine Cr)`
    • Confirm FHH with CASR sequencing and by testing relatives - an unnecessary parathyroidectomy is the classic error
Once primary hyperparathyroidism is confirmed - assess end-organ damage
  • DEXA including the distal 1/3 radius (cortical site - PTH preferentially damages cortical bone; the spine may look normal)
  • Vertebral fracture assessment; renal tract imaging for silent stones/nephrocalcinosis
  • 24-hour urinary calcium, eGFR
  • Genetic testing if <40y, multigland disease, or family history (MEN1, MEN2A, MEN4, CDC73/HPT-jaw tumour)
Localisation - only after the biochemical diagnosis, and only if operating
  • Sestamibi-SPECT/CT + neck ultrasound; 4D-CT or 18F-fluorocholine PET if discordant
  • Imaging never makes the diagnosis - it plans the incision

Management1 exam ›

Acute severe hypercalcaemia (>3.5, or symptomatic)
  • 1. Volume repletion - the first and most important step
    • 0.9% saline 200-500 mL/h initially, 3-6 L in the first 24h, guided by cardiac and renal status
    • Corrects the vasopressin-resistant polyuria and restores GFR -> calciuresis
    • Loop diuretic only for fluid overload - not a calcium-lowering treatment, and harmful if given before rehydration
  • 2. Antiresorptive - the definitive step, but slow
    • Zoledronic acid 4 mg IV (adjust for renal function) - onset 2-4 days, nadir at 4-7 days, lasts weeks
    • Denosumab 120 mg SC - 2023 Endocrine Society guidance now prefers denosumab over IV bisphosphonate first-line in hypercalcaemia of malignancy, and it is the agent of choice in renal impairment and in bisphosphonate-refractory or recurrent disease
      • Beware profound and prolonged hypocalcaemia, especially with vitamin D deficiency or CKD
  • 3. Calcitonin 4 units/kg SC/IM 12-hourly - works within hours, tachyphylaxis by 48h. A bridge while the antiresorptive takes effect
  • 4. Glucocorticoid - prednisolone 20-40 mg/day for calcitriol-mediated hypercalcaemia: granulomatous disease, lymphoma, vitamin D intoxication
    • Inhibits 1-alpha-hydroxylase and induces 24-hydroxylase -> dec calcitriol
    • Ineffective in primary HPT and in PTHrP-mediated disease
  • 5. Dialysis for severe hypercalcaemia with renal failure, heart failure, or neurological compromise
  • Stop the contributors: thiazide, lithium, calcium and vitamin D supplements, teriparatide; mobilise; withhold digoxin
Primary hyperparathyroidism
  • Parathyroidectomy is the only cure
  • Surgery if ANY ONE of (Fifth International Workshop 2022)
    • Symptomatic disease - fracture, stone, overt hypercalcaemia
    • Age <50
    • Calcium >0.25 mmol/L above the upper limit of normal
    • T-score <=-2.5 at any site, or a vertebral fracture on imaging
    • eGFR <60, nephrolithiasis or nephrocalcinosis on imaging, or 24h urine calcium >10 mmol/day with increased stone risk
    • Also reasonable in anyone who prefers surgery, or for whom surveillance is not feasible
  • Not for surgery -> monitor: annual calcium and creatinine, DEXA every 1-2 years
    • Maintain adequate hydration and normal dietary calcium (restriction paradoxically raises PTH)
    • Replete vitamin D to >50 nmol/L - safe and lowers PTH
  • Medical therapy where surgery is not possible
    • Cinacalcet (calcimimetic) - lowers calcium, does not improve BMD
    • Bisphosphonate or denosumab - improves BMD, does not lower calcium much
    • The two do different jobs - pick by whether the problem is the calcium or the bone
FHH
  • *No treatment. No surgery.* Reassure, and label the file clearly
Malignancy
  • Treat the tumour - hypercalcaemia recurs relentlessly otherwise
  • Repeat denosumab or zoledronic acid; consider goals of care

Associations

  • MEN1 (parathyroid + pituitary + pancreatic NET), MEN2A (with MTC and phaeo), MEN4 (CDKN1B)
  • HPT-jaw tumour syndrome (CDC73/HRPT2) - strongly associated with parathyroid carcinoma; test anyone young with severe disease
  • Lithium, thiazides
  • Sarcoidosis, TB, granulomatosis with polyangiitis
  • Myeloma, breast, lung (squamous), renal cell, lymphoma
  • Nephrogenic diabetes insipidus, pancreatitis, peptic ulcer (Zollinger-Ellison in MEN1)
  • Osteitis fibrosa cystica - brown tumours, subperiosteal resorption of the radial phalanges, "pepper-pot" skull, now rare

Natural history & complications

  • Mild asymptomatic primary HPT is often stable for years; ~1/3 progress over 10-15 years
    • Progression risk highest if age <50
    • Cortical bone loss (distal radius, hip) continues even when the spine is preserved
  • Parathyroidectomy: cure rate >95% in expert hands; BMD improves substantially in the first 1-2 years
    • Hungry bone syndrome after removal of a large adenoma - profound, prolonged hypocalcaemia; anticipate with high ALP and large adenoma
  • Hypercalcaemia of malignancy is a marker of advanced disease - median survival historically ~30 days untreated, and still only months
  • Untreated severe hypercalcaemia -> AKI, arrhythmia, coma, death
  • Parathyroid carcinoma - very high calcium (often >3.5) + palpable neck mass + very high PTH; recurrence is the rule

7 of 7 sections written · drafted 2026-09-03