Hypercalcemia

Hypercalcemia: Clinical & Diagnostic Overview

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I. Clinical Features of Hypercalcemia

• General: fatigue, muscle weakness

• Neurologic/Psychiatric: confusion, lethargy, depression, psychosis, coma (in severe cases)

• Gastrointestinal: anorexia, nausea, constipation, abdominal pain, pancreatitis, peptic ulcers

• Renal:

  • Polyuria & polydipsia (due to nephrogenic diabetes insipidus effect)

  • Dehydration/volume depletion

  • Nephrolithiasis ("stones")

• Cardiac: shortened QT interval, arrhythmias

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II. Causes of Hypercalcemia

1. Primary hyperparathyroidism (PHPT) – parathyroid adenoma/hyperplasia

2. Malignancy-related hypercalcemia – most common cause in hospitalized patients

   • PTHrP secretion (squamous cell carcinoma)

   • Bone metastases (breast, lung, myeloma)

   • ↑ Calcitriol (lymphoma)

3. Vitamin D intoxication

4. Granulomatous disease (sarcoidosis, TB) – increased 1,25-dihydroxyvitamin D

5. Medications – thiazides, lithium

6. Familial hypocalciuric hypercalcemia (FHH) – CaSR mutation

7. Endocrine disorders – thyrotoxicosis, adrenal insufficiency

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III. Acute Management of Severe Hypercalcemia (Ca²⁺ >14 mg/dL or symptomatic)

1. IV Normal saline (0.9%) hydration

   • Restores volume → enhances renal calcium clearance.

2. Calcitonin

   • Rapid onset (4–6 hrs), but tachyphylaxis within 2–3 days.

3. Bisphosphonates (e.g., zoledronic acid, pamidronate)

   • Onset: 2–4 days, effect lasts weeks.

   • Inhibit osteoclast-mediated bone resorption.

   • Main long-term therapy for malignancy-induced hypercalcemia.

4. Loop diuretics (furosemide) – only if volume overload after rehydration.

5. Dialysis – reserved for refractory cases or renal failure.

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IV. Familial Hypocalciuric Hypercalcemia (FHH)

• Pathophysiology:

  • Inactivating mutation of calcium-sensing receptor (CaSR) in kidney & parathyroid glands →
    kidneys perceive serum calcium as “low” → less calcium excretion & higher PTH set point.

• Clinical:

  • Lifelong, mild hypercalcemia

  • Usually asymptomatic

  • Family history often positive

• Lab findings:

  • Serum calcium: mildly ↑ (usually <12 mg/dL)

  • PTH: normal or mildly ↑

  • Urinary calcium excretion: low

  • Urine calcium/creatinine clearance ratio (UCCR):

    • <0.01 → FHH

• Management:

  • Benign, no treatment required.

  • Differentiate from PHPT to avoid unnecessary parathyroidectomy.

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V. Primary Hyperparathyroidism (PHPT)

• Pathophysiology:

  • Excess PTH secretion (adenoma, hyperplasia, carcinoma).

• Clinical features: "Stones, bones, abdominal groans, psychiatric overtones"

  • Nephrolithiasis, osteoporosis/osteitis fibrosa cystica, constipation/ulcers, psychiatric changes.

• Lab findings:

  • Serum calcium: ↑

  • PTH: ↑

  • Urinary calcium excretion: ↑

  • UCCR >0.02

• Management:

  • Parathyroidectomy in symptomatic or high-risk patients.

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VI. Malignancy-Associated Hypercalcemia

• Mechanisms:

  1. PTHrP secretion – squamous cell carcinoma of lung, renal, bladder, ovarian carcinoma.

  2. Bone metastases/osteolysis – breast, lung, multiple myeloma.

  3. ↑ Calcitriol – lymphoma, granulomatous disease.

• Clinical:

  • More acute, severe hypercalcemia (Ca²⁺ often >14).

  • Rapid progression with profound symptoms.

• Lab findings:

  • PTH: suppressed (low)

  • PTHrP: ↑ (if measured)

  • Vitamin D metabolites: variable

• Management:

  • Saline + calcitonin + bisphosphonates (definitive).

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VII. Key Comparison Table

Feature	FHH	PHPT	Malignancy
Onset	Lifelong, incidental	Gradual, chronic	Acute, often severe
Symptoms	Asymptomatic	Stones, bones, groans, psychiatric	Severe confusion, dehydration, weakness
Serum Ca²⁺	Mild ↑ (<12)	Mild–moderate ↑	Often severe (>14)
PTH	Normal / mildly ↑	↑	Suppressed
Urine Ca²⁺	Low	High	Variable (usually high)
UCCR	<0.01	>0.02	–
Family history	Often positive	Sporadic	None
Management	None	Surgery if symptomatic/high-risk	Treat underlying cancer + bisphosphonates

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✅ Key Exam Pearls:

• Always check urine calcium excretion (UCCR) to differentiate FHH from PHPT.

• Severe hypercalcemia (>14 or symptomatic): saline hydration + calcitonin (fast), bisphosphonates (sustained).

• Hospital setting: malignancy is the most common cause.