Makindo Medical Notes

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

• Parathyroid hormone related peptide (PTHrP): a mini-review