Related Subjects:
|Lung Cancer
|Hypercalcaemia
|Oncological emergencies
|Malignant Hyperparathyroidism due to PTHrP
|Lambert-Eaton syndrome (LEMS)
|Superior Vena Caval Obstruction syndrome
|Syndrome of Inappropriate ADH (SIADH) secretion
🧪 If a patient is hypercalcaemic with a raised PTHrP, there is a ~99% chance of underlying malignancy – it is highly specific.
At physiological low levels, PTHrP has mostly paracrine and autocrine roles, vital in embryonic, fetal, and postnatal development.
📍 About
- Parathyroid hormone–related peptide (PTHrP) is normally produced in very small amounts by many tissues.
- Encoded by a single gene on the short arm of chromosome 12.
- Structurally similar to PTH at the amino-terminal end, allowing it to activate PTH receptors.
🧬 Aetiology & Pathophysiology
- Physiologically: regulates maternal–fetal calcium transport in pregnancy and plays a role in smooth muscle relaxation, placental calcium transfer, and bone development.
- Pathologically: tumours secrete PTHrP, mimicking PTH → ↑ bone resorption + ↑ renal calcium reabsorption → hypercalcaemia of malignancy.
- Unlike primary hyperparathyroidism, PTH is suppressed because high calcium feeds back to the parathyroids.
⚠️ Causes (Malignancies commonly linked with PTHrP)
- 🚬 Squamous cell carcinoma of the lung (classic cause).
- 🎀 Breast cancer.
- 🩸 Renal cell carcinoma.
- Less common: head and neck cancers, ovarian cancer, bladder cancer.
🩺 Clinical Features
- Symptoms of hypercalcaemia: “stones, bones, groans, and psychiatric overtones” (renal stones, bone pain, GI upset, mood changes, confusion).
- Often rapid onset, more severe than primary hyperparathyroidism.
- Additional tumour-related symptoms: cough, haemoptysis, breast mass, haematuria etc., depending on site.
🔬 Investigations
- 🧪 Bloods:
- Corrected calcium ↑
- PTH ↓ (suppressed)
- PTHrP ↑ (>1.4 pmol/L)
- Phosphate often low
- 📸 Imaging:
- CXR (look for lung cancer).
- CT chest/abdomen/pelvis (search for solid tumours).
- 🧬 Consider myeloma screen (to rule out alternative hypercalcaemia mechanisms).
💊 Management
- 🚑 Initial: ABC + IV hydration (normal saline) to enhance calciuresis.
- 💉 Bisphosphonates (e.g. IV zoledronic acid, pamidronate) inhibit osteoclast-mediated bone resorption.
- 🌡️ Calcitonin for rapid but short-lived calcium reduction (useful in severe/symptomatic cases).
- 🧪 Treat underlying malignancy (oncology input crucial).
- In refractory cases: denosumab (anti-RANKL mAb) may be considered.
📚 Teaching Pearls
- 🔑 PTHrP-driven hypercalcaemia = “humoral hypercalcaemia of malignancy” - the most common paraneoplastic endocrine syndrome.
- Differentiate from primary hyperparathyroidism:
• Malignancy → ↑ Ca²⁺ + ↑ PTHrP + ↓ PTH.
• Primary HPT → ↑ Ca²⁺ + ↑ PTH.
- Hypercalcaemia in malignancy is a poor prognostic marker - often late stage.
🔗 References
