Hypercalcaemia: A Diagnostic Approach

PATHCHAT Edition No. 57
June 2019
Please contact your local Ampath pathologist for more information.

Author: Dr. Devina Govender

Introduction

✅ What is Hypercalcaemia?

• Hypercalcaemia is a common clinical problem.
• Primary hyperparathyroidism and malignancy account for >90% of cases.
• Diagnosis involves distinguishing between parathyroid-mediated and non-parathyroid causes.

✅ Definition of Hypercalcaemia:

• Normal calcium range: 2.15–2.50 mmol/L.
• Hypercalcaemia: Serum calcium >2.50 mmol/L.

✅ Calcium Correction Factors:

• 40% of calcium is protein-bound (mainly albumin).
• Ionized calcium represents the biologically active fraction.
• Ionized calcium should be assessed in patients with albumin or acid-base disturbances.

📌 Mild hypercalcaemia is often detected incidentally, whereas severe hypercalcaemia is usually symptomatic.

Clinical Presentation of Hypercalcaemia

✅ Symptoms (Classic "Moans, Bones, Stones, and Groans"):

✔ Neurological & Psychiatric ("Moans")

• Fatigue.
• Depressed mood or confusion.
• Delirium or coma in severe cases.

✔ Skeletal Symptoms ("Bones")

• Pathological fractures.
• Bone pain.
• Osteitis fibrosa cystica (rare in severe primary hyperparathyroidism).

✔ Renal Symptoms ("Stones")

• Polyuria and polydipsia (nephrogenic diabetes insipidus).
• Nephrocalcinosis.
• Kidney stones (nephrolithiasis).

✔ Gastrointestinal Symptoms ("Groans")

• Nausea, vomiting.
• Constipation, peptic ulcer disease.
• Pancreatitis.

📌 Severe hypercalcaemia (>3.25 mmol/L) can cause life-threatening cardiac arrhythmias.

Causes of Hypercalcaemia

✅ Parathyroid-Mediated Hypercalcaemia:

• Primary hyperparathyroidism (sporadic).
• Inherited forms of hyperparathyroidism:
  • Multiple Endocrine Neoplasia (MEN) type 1 & 2a.
  • Familial isolated hyperparathyroidism.
  • Hyperparathyroidism-jaw tumor syndrome.
• Familial hypocalciuric hypercalcaemia (FHH).
• Tertiary hyperparathyroidism (secondary to renal failure).

✅ Non-Parathyroid Mediated Hypercalcaemia:
✔ Malignancy-Associated Hypercalcaemia:

• PTH-related peptide (PTHrP) secretion.
• Increased calcitriol (1,25-dihydroxyvitamin D).
• Osteolytic bone metastases with local cytokine activation.

✔ Vitamin D-Related Causes:

• Vitamin D intoxication.
• Chronic granulomatous disorders (sarcoidosis, tuberculosis, lymphoma).

✔ Medication-Induced Hypercalcaemia:

• Thiazide diuretics.
• Lithium.
• Recombinant PTH (e.g., teriparatide).
• Excessive vitamin A.
• Theophylline toxicity.

✔ Endocrine Disorders & Other Causes:

• Hyperthyroidism.
• Acromegaly.
• Phaeochromocytoma.
• Adrenal insufficiency.
• Immobilisation.
• Parenteral nutrition.
• Milk-alkali syndrome.

📌 A careful history and biochemical testing help differentiate between these causes.

Diagnostic Approach to Hypercalcaemia

✅ Stepwise Evaluation:

1. Confirm hypercalcaemia with repeat measurement of serum calcium.
2. Assess serum parathyroid hormone (PTH) to distinguish PTH-mediated from non-PTH-mediated causes.

🔹 Interpretation of PTH Levels in Hypercalcaemia:

✔ Elevated PTH:

• Primary hyperparathyroidism (most common).
• Familial hypocalciuric hypercalcaemia (FHH) (consider urine calcium excretion testing).

✔ Low or Suppressed PTH:

• Suggests non-PTH mediated hypercalcaemia.
• Perform additional tests:
  • PTH-related peptide (PTHrP) (suspected malignancy).
  • Vitamin D metabolites (1,25-dihydroxyvitamin D for granulomatous disease or lymphoma).
  • 25-hydroxyvitamin D (for vitamin D intoxication).
  • Thyroid function tests (hyperthyroidism).
  • Serum protein electrophoresis (multiple myeloma).

📌 Hypercalcaemia in hospitalized patients is often malignancy-related, while in outpatients, primary hyperparathyroidism is more common.

Laboratory Tests for Hypercalcaemia

✅ Essential Tests:

• Serum calcium (corrected for albumin).
• Ionized calcium (if albumin abnormalities present).
• PTH (to differentiate PTH-mediated vs. non-PTH-mediated hypercalcaemia).
• Phosphate (low in PTH-mediated hypercalcaemia).
• Creatinine & eGFR (renal function assessment).

✅ Additional Tests Based on Clinical Suspicion:

• 24-hour urinary calcium (distinguishes primary hyperparathyroidism from FHH).
• PTHrP (if malignancy is suspected).
• 1,25-dihydroxyvitamin D (if granulomatous disease or lymphoma suspected).
• 25-hydroxyvitamin D (for vitamin D intoxication).
• Serum protein electrophoresis (SPEP) & urine protein electrophoresis (UPEP) (for multiple myeloma).
• Serum free light chains & immunofixation (for plasma cell disorders).
• Vitamin A levels (for hypervitaminosis A).

📌 The combination of PTH measurement and vitamin D metabolites is key to diagnosing hypercalcaemia.

Key Takeaways for Clinicians

✅ Primary hyperparathyroidism and malignancy are the most common causes of hypercalcaemia.
✅ Serum PTH measurement is the initial test to differentiate between PTH-mediated and non-PTH-mediated causes.
✅ Non-PTH-mediated hypercalcaemia requires additional workup, including vitamin D metabolites, SPEP, and PTHrP.
✅ Hypercalcaemia-related complications include nephrolithiasis, renal failure, arrhythmias, and neurological symptoms.
✅ 24-hour urinary calcium measurement helps differentiate primary hyperparathyroidism from familial hypocalciuric hypercalcaemia (FHH).

📌 Early identification of the underlying cause is crucial for appropriate management and prevention of complications.