Makindo Medical Notes

Related Subjects: | Familial Hypocalciuric Hypercalcaemia (FHH) | Primary Hyperparathyroidism | Lung Cancer | Hypercalcaemia | Multiple Myeloma | Oncological Emergencies | Bisphosphonates

An albumin-adjusted serum calcium level above 2.6 mmol/L (UK) is considered hypercalcemia. More than 90% of cases are due to malignancy or primary hyperparathyroidism.

Initial Hypercalcemia: Total Serum Calcium >10.5 mg/dL (2.6 mmol/L).

ABC. Oral hydration (3-4 L/day) for euvolemic patients with Ca²⁺ < 3.0 mmol/L (12.0 mg/dL). If moderate to severe hypercalcemia and patient is dehydrated, administer 4-6 L N-Saline IV over 24 hours. Caution: Limit fluids to 2-3 L/day in patients at risk of heart failure. Identify and treat the underlying cause. Check Ca²⁺, phosphate, ALP, PTH, CXR, ESR, and PPE. After hydration, if calcium remains elevated, consider: IV Zoledronate 4 mg in 100 ml NaCl 0.9% over 15 minutes, or IV Pamidronate 60-90 mg over 2 hours (or 4-5 hours if renal failure), depending on serum calcium levels. Pamidronate dosage based on Ca²⁺ levels: Ca²⁺ < 3.0 mmol/L: 15-30 mg Ca²⁺ 3.0-3.5 mmol/L: 30-60 mg Ca²⁺ 3.5-4.0 mmol/L: 60-90 mg Ca²⁺ >4.0 mmol/L: 90 mg Steroids (e.g., Prednisolone 40-60 mg OD) may be useful in conditions such as sarcoidosis—consult a specialist.

Calcium Levels: To convert from mg/dL (US) to mmol/L (UK), multiply by 0.25

Measurement	US Units (mg/dL)	UK Units (mmol/L)
Normal Range	8.5 - 10.5 mg/dL	2.12 - 2.62 mmol/L
Hypocalcemia	< 8.5 mg/dL	< 2.12 mmol/L
Hypercalcemia	> 10.5 mg/dL	> 2.62 mmol/L

Aetiology

• Free ionized calcium (Ca²⁺) is biologically active, but difficult to measure, so total calcium is usually measured.
• Albumin, citrate, and phosphate bind unionized calcium, so low albumin gives a falsely low calcium level, and vice versa.
• Acidosis decreases protein binding sites, increasing ionized calcium, while alkalosis increases protein binding, reducing ionized calcium.
• Most calcium (1-2 kg) is stored in bone, released into the bloodstream during hypocalcemia through the action of parathyroid hormone (PTH).

Causes

Cause	Clinical Features	Investigations	Management
Primary Hyperparathyroidism	Often asymptomatic; may present with bone pain, fractures, nephrolithiasis, polyuria, constipation, and mental disturbances ("stones, bones, abdominal groans, and psychiatric overtones").	Elevated serum calcium, elevated or inappropriately normal PTH, low serum phosphate, increased urinary calcium excretion.	Surgical removal of overactive parathyroid gland(s), hydration, bisphosphonates for bone protection, monitoring in mild cases.
Malignancy-Associated Hypercalcemia	Symptoms of advanced malignancy, such as weight loss, fatigue, bone pain, polyuria, dehydration, and confusion.	Elevated serum calcium, suppressed PTH, elevated PTHrP in humoral hypercalcemia, imaging to identify primary tumour/metastases.	IV fluids, bisphosphonates, denosumab, treat underlying malignancy, corticosteroids in select cases.
Vitamin D Toxicity	Symptoms include nausea, vomiting, polyuria, dehydration, and confusion, often related to excessive vitamin D/calcium intake.	Elevated serum calcium, elevated 25-hydroxyvitamin D, suppressed PTH, normal or elevated phosphate.	Discontinue vitamin D and calcium, hydration, corticosteroids, bisphosphonates in severe cases.
Sarcoidosis / Granulomatous Diseases	Symptoms of hypercalcemia, such as polyuria and fatigue; may also present with respiratory issues in sarcoidosis.	Elevated serum calcium, elevated 1,25-dihydroxyvitamin D, suppressed PTH, imaging/biopsy for granulomas.	Corticosteroids to reduce granulomas, hydration, bisphosphonates in severe cases.
Thiazide Diuretics	Mild, asymptomatic hypercalcemia; may exacerbate underlying hyperparathyroidism.	Elevated serum calcium, suppressed PTH, history of thiazide use, exclusion of other causes.	Discontinue thiazide, monitor calcium levels, treat underlying conditions.
Familial Hypocalciuric Hypercalcemia (FHH)	Mild hypercalcemia, often asymptomatic, family history of hypercalcemia; typically presents in childhood or early adulthood.	Elevated serum calcium, low urinary calcium, genetic testing for CASR mutations, normal/mildly elevated PTH.	No treatment required; genetic counseling may be offered.
Immobilization	Hypercalcemia in patients with prolonged immobilization, particularly those with high bone turnover (e.g., Paget's disease, adolescents).	Elevated serum calcium, normal/suppressed PTH, history of immobilization, elevated bone turnover markers.	Increased mobility, bisphosphonates, hydration.
Hyperthyroidism	Symptoms of hyperthyroidism (e.g., weight loss, tachycardia) with mild hypercalcemia.	Elevated serum calcium, suppressed PTH, elevated thyroid hormones (T3, T4), suppressed TSH.	Treat hyperthyroidism, hydration, bisphosphonates if severe.

Clinical Features: "Bones, Stones, Groans, Moans"

• Bones: Bone pain, fractures, metastases, myeloma.
• Stones: Kidney stones, polyuria, polydipsia.
• Groans: Abdominal pain, constipation, nausea, vomiting, pancreatitis, peptic ulcer disease.
• Moans: Confusion, depression, delirium, psychosis, coma.
• Other: Hypotonia, hyporeflexia, weakness, tongue fasciculations, hypertension, and long-standing hypercalcemia can lead to band keratopathy.

Investigations

• FBC: Anemia (myeloma, cancer, renal disease).
• U&E: Dehydration, renal failure (myeloma), raised serum calcium.
• ↑ ESR: Myeloma, malignancy.
• ECG: Short QT interval.
• CXR: Squamous cell carcinoma, BHL, and fibrosis (sarcoidosis).
• 24-hr Urinary Calcium: Usually elevated except in milk-alkali syndrome, thiazide use, or FHH (low urinary calcium).
• PTH: Inappropriately normal/elevated in primary hyperparathyroidism, low in malignancy-related hypercalcemia.
• Isotope bone scan and PTHrP (in malignancy).
• Vitamin D, ACE levels (if sarcoidosis is suspected).

Management

• Hydration is the primary focus due to calcium-induced polyuria; patients may need 4-6 L of 0.9% saline over 24 hours.
• Furosemide can be given after adequate hydration to promote calcium clearance.
• Bisphosphonates such as pamidronate (60-90 mg IV) or zoledronic acid (4 mg IV) may be administered once hydration is ensured.
• Consider corticosteroids (e.g., prednisolone 40-60 mg OD) in conditions like sarcoidosis or lymphoma.
• Calcitonin and dialysis may be considered in refractory cases.

References

• Hypercalcemia Guideline for Primary Care