Hypercalcaemia

Introduction

Hypercalcaemia, characterised by elevated calcium levels in the blood, can have diverse clinical effects, ranging from mild fatigue to life-threatening complications. Calcium is tightly regulated by parathyroid hormone (PTH), vitamin D, and renal function, making it critical to identify and treat the underlying cause of hypercalcaemia.

Clinical Manifestations of Hypercalcaemia

The symptoms of hypercalcaemia often manifest across multiple systems and can range from mild to severe depending on how quickly calcium levels rise.

  • "Stones": Nephrolithiasis (kidney stones) due to increased urinary calcium excretion, leading to renal colic.
  • "Bones": Bone pain resulting from increased bone resorption.
  • "Groans": Gastrointestinal symptoms such as abdominal pain, constipation, anorexia, and nausea.
  • "Psychiatric Overtones": Neurological effects like depression, anxiety, confusion, or psychosis.

Additional Symptoms:

  • Weakness, fatigue, lethargy.
  • Severe Symptoms: Polyuria, polydipsia (nephrogenic diabetes insipidus), dehydration, and even coma.

Key ECG findings in hypercalcaemia include:

  1. Short QT interval: A hallmark finding due to the shortened ST segment.
  2. ST segment elevation: Can mimic myocardial infarction and lead to unnecessary interventions.
  3. Osborne wave: Rare, but seen in significant calcium disturbances.

Corrected Calcium for Albumin

As calcium binds to albumin, total serum calcium levels can be misleading in patients with abnormal albumin levels. Corrected calcium provides a more accurate reflection of the biologically active ionised calcium.

The formula for corrected calcium is:

Corrected Calcium (mg/dL)=Measured Calcium (mg/dL)+0.8×(4.0−Albumin (g/dL))\text{Corrected Calcium (mg/dL)} = \text{Measured Calcium (mg/dL)} + 0.8 \times (4.0 - \text{Albumin (g/dL)})

For mmol/L, the correction factor is 0.02 mmol/L per 1 g/L decrease in albumin below 40 g/L.

This formula is particularly useful when ionised calcium is not readily available.

Aetiologies of Hypercalcaemia

Hypercalcaemia can be broadly divided into PTH-dependent and PTH-independent causes:

Category Aetiology Description
PTH-Dependent Primary hyperparathyroidism Most common cause of hypercalcaemia, often due to a parathyroid adenoma.
Tertiary hyperparathyroidism Seen in CKD, where overactive parathyroid glands persist despite correction of calcium levels.
Familial hypocalciuric hypercalcaemia Genetic condition with a benign course, caused by reduced sensitivity of calcium-sensing receptors.
PTH-Independent Malignancy-related hypercalcaemia Often due to PTHrP (parathyroid hormone-related protein) secretion, common in lung and breast cancers.
Osteolytic metastases Seen in cancers like multiple myeloma and breast cancer, which destroy bone.
Vitamin D intoxication Excessive vitamin D intake or ectopic production (e.g. in sarcoidosis).
Milk-alkali syndrome Excessive intake of calcium carbonate (often with antacids) leading to metabolic alkalosis and hypercalcaemia.
Granulomatous diseases Sarcoidosis, tuberculosis, and other granulomatous conditions lead to excessive production of calcitriol.
Drug-induced Thiazide diuretics, lithium, and excessive vitamin D can increase calcium levels.

Key Mechanisms:

  • PTH-dependent hypercalcaemia is primarily driven by excess PTH production.
  • PTH-independent hypercalcaemia involves other mechanisms like malignancy, granulomatous disease, or vitamin D excess.

Diagnostic Approach

A structured approach is essential to confirm hypercalcaemia and determine its cause:

  1. Correct serum calcium for albumin.
  2. Measure PTH:
    • Elevated PTH: Suggests primary hyperparathyroidism, familial hypocalciuric hypercalcaemia, or tertiary hyperparathyroidism.
    • Suppressed PTH: Suggests PTH-independent causes, such as malignancy or vitamin D excess.
  3. Assess for malignancy: Obtain chest X-ray or CT scan to look for cancers (e.g., lung, breast) or granulomatous diseases.
  4. Other Tests:
    • PTHrP: To confirm paraneoplastic hypercalcaemia.
    • Calcitriol and calcidiol: To assess vitamin D metabolism.
    • 24-hour urine calcium: Low urinary calcium may suggest familial hypocalciuric hypercalcaemia (FHH).
    • Creatinine: To assess kidney function, especially in CKD-related hypercalcaemia.

Typical lab findings in hypercalcaemia:

Condition PTH PTHrP Vitamin D Calcium
Primary hyperparathyroidism High Normal Normal High
Malignancy (PTHrP) Low High Normal High
Vitamin D intoxication Low Normal High High
Granulomatous disease Low Normal High High

Treatment Strategies

Management of hypercalcaemia focuses on lowering calcium levels and treating the underlying cause. The approach depends on the severity of hypercalcaemia and the patient's symptoms.

  1. Hydration with Normal Saline:
    • IV saline is essential to rehydrate and increase calcium excretion through the kidneys.
    • Initial rates of 150–500 mL/hour until euvolaemia is restored are typical.
  2. Loop Diuretics (e.g. Furosemide):
    • After rehydration, furosemide can promote calcium excretion by inhibiting reabsorption in the renal tubules.
  3. Bisphosphonates:
    • Inhibit osteoclast-mediated bone resorption.
    • Zoledronic acid or pamidronate are commonly used, especially in malignancy-related hypercalcaemia.
    • Onset: 1–2 days; Duration: 2–4 weeks.
  4. Calcitonin:
    • Rapidly decreases serum calcium by inhibiting osteoclast activity.
    • Onset: 4–6 hours, but the effect is transient (lasting 1–2 days) due to tachyphylaxis.
  5. Steroids:
    • Effective in granulomatous diseases (e.g., sarcoidosis, lymphoma) by reducing calcitriol production.
    • Typical doses: Prednisone 10–40 mg daily.
  6. Gallium Nitrate:
    • Inhibits bone resorption and PTH secretion.
    • Onset: 1–2 days, but carries a risk of nephrotoxicity.
  7. Denosumab:
    • A monoclonal antibody that inhibits osteoclast function, used in refractory hypercalcaemia, particularly in malignancy.
    • Onset: 1–4 days, effective in patients resistant to bisphosphonates.

Summary of Treatment Options:

Treatment Onset Duration Side Effects
Normal Saline 1–2 hours Immediate Volume overload.
Furosemide 1–2 hours During treatment Electrolyte imbalances (hypokalaemia).
Bisphosphonates 1–2 days 2–4 weeks Acute kidney injury, osteonecrosis of the jaw.
Calcitonin 4–6 hours 1–2 days Tachyphylaxis.
Steroids 2–4 days Several weeks Hyperglycaemia, fluid retention.
Gallium Nitrate 1–2 days 2 weeks Nephrotoxicity.