Hypercalcaemia

Hypercalcaemia (serum calcium >2.5mmol/L) is a common and occasionally severe electrolyte disorder.

No formal severity grading exists, but a reasonable stratification is:

Mild: 2.6-2.9mmol/L
Often asymptomatic, urgent correction not required.
Moderate: 3.0-3.4mmol/L
Acute occurrence often symptomatic and demands prompt treatment.
Severe: >3.4mmol/L
Urgent treatment required due to risk of dysrhythmias.

Extracellular calcium is split (approximately evenly) into:

Ionised calcium (1.1-1.3mmol/L)
Only biologically important version as bound calcium is not active.
- Ionised calcium is affected by pH, as an ↑ in H⁺ concentration displaces calcium from albumin and therefore ↑ iCa²⁺
  For every 0.1 ↓ in pH, iCa²⁺ ↑ by ~0.05mmol/L.
Bound calcium
- Majority (90%) of non-ionised calcium is bound to albumin, and so total calcium is affected by albumin levels
- Remainder bound to beta-globulins, phosphate, citrate, sulphate, ketones
  Generally of little clinical importance.

Epidemiology and Risk Factors

Hypercalcaemia of malignancy is:
- Common (20-30%)
- Associated with poor prognosis

Pathophysiology

Calcium is an important cation with multiple critical functions:

Muscular contraction
Coagulation
Neurotransmission
Hormone release
Cellular apoptosis

Calcium homeostasis is regulated by:

PTH
- Release stimulated by ↓ serum calcium and magnesium
- ↑ Renal and bone reabsorption
- ↑ Calcitriol production
  ↑ Gut calcium absorption.
Vitamin D
Calcitriol precursor.
Calcitonin
Functionally a PTH antagonist.
- Release stimulated by hypercalcaemia, catecholamines, and gastrin
- ↓ Bone reabsorption and ↑ renal elimination

Hypercalcaemia occurs most commonly when osteoclastic resorption or GI absorption exceed the ability of the kidney to eliminate it or the skeleton to claim it.

Aetiology

Common causes:

Malignancy and primary hyperparathyroidism account for >90% of cases.

↑ PTH
- Primary hyperparathyroidism
  Adenoma.
↓ PTH
- Malignancy
  - Lytic bone lesions
    - Haematological malignancy/myeloma
    - Breast cancer
    - Paget’s disease
  - ↑ PTHrP
    Paraneoplastic syndrome from:
    - Squamous cell tumours Lung, head and neck.
    - Other tumours
      Renal, transitional, breast, prostate, colon, ovarian cancer.
- Drugs
  - Thiazide
  - Lithium
  - Oestrogen/HRT
  - TPN
- Other
  - Immobilisation
  - TLS
  - Hypovolaemia

Uncommon causes:

↓ PTH
- Endocrine
  - Thyrotoxicosis
  - Addison’s disease
  - Phaeochromocytoma
  - Gastric adenoma
- ↑ 25-hydroxyvitamin D
  Dietary vitamin D that has been activated by hepatic metabolism.
  - Excess Vitamin D intake
  - Lymphoma
- ↑ 1,25-dihydroxyvitamin D
  Calcitriol, produced in the renal tubule from 25-hydroxyvitamin D.
  - Extra-renal production
    Classically granulomatous disease.
    - HIV
    - Sarcoid
    - Tuberculosis
    - Histoplasmosis
    - Coccidioidomycosis
    - Leprosy
- Drugs
  - Androgens
  - Theophylline
  - TPN
- Other
  - CKD
    Secondary hyperparathyroidism.
  - Tertiary hyperparathyroidism
  - Hypophosphataemia
  - Rhabdomyolysis
    Usually preceded by a hypocalcaemic state.
  - Milk alkali syndrome

Clinical Manifestations

Include:

Classically, “stones, bones, groans, and psychic moans.”

C
- HTN
- Short QT
- AV block
- Broad QRS
- Osborn Waves
- Malignant arrhythmias
D
- Delirium
- Headache
- Seizures
E
- Weakness
- Bone pain
F
- Polydipsia
- Polyuria
  - DI
    Secondary to interfering with ADH action in the DCT.
- Type 1 RTA
- Nephrolithiasis
- Renal failure
G
- Nausea
- Pancreatitis
- Peptic ulcers

Diagnostic Approach and DDx

Investigations

Bedside:

Laboratory:

Three equations exist to correct measured calcium:

Correction of ionised calcium for pH:
\(iCa^{2+}_{7.4}c = iCa^{2+} \times (1 - 0.53 \times (7.40 - pH))\)
Correcting total calcium for:
- Albumin:
  Measured total calcium will ↓ (or ↑) by 0.02 mmol/L for every 1g/L ↓ (or ↑) the albumin is above 40g/L.
- Globulins:
  Measured total calcium will ↓ (or ↑) by 0.04mmol/L for every 10g/L ↓ (or ↑) in serum globulin.

Bloods
- UEC
  Renal failure.
- Mg
- PTH
- ALP
- Lipase
- PTHrP
  Rule out humoral hypercalcaemia of malignancy.
- 1,25-dihydroxy vitamin D
- 25-hydroxy vitamin D
  Rule out vitamin D intoxication.
- TSH

Other:

Urinary calcium
Hypercalciuria usually precedes hypercalcaemia, as hypercalcaemia only occurs when renal elimination is overwhelmed.
ECG

Management

Resuscitation:

Do not give thiazide diuretics, this will worsen hypocalcaemia.

Volume expansion To dilute serum calcium and promote renal clearance. Start at NS 250mL/hr.
Correct magnesium and potassium
↓ Renal resorption
- Loop diuretics
  Not useful for reducing serum calcium but are useful for controlling for volume overload.
↓ Bone reabsorption
- Bisphosphonates
  Works over 2-3 days.
  - Pamindronate 60-90mg IV
- Zoledronic acid 4mg IV
  Alternative to bisphosphonates.
- Calcitonin/Salcalcitonin
  Rapid and transient effect. Most useful in severe hypercalcaemia whilst waiting bisphosphonate therapy to work.
RRT
If cardiac/renal compromise.

Loop diuretics were used historically to enhance elimination of calcium, but this is probably ineffective. They are still used to control volume state, however.

Specific therapy:

Pharmacological
- Hydrocortisone 100mg QID
  Useful in granulomatous disease. ↓ Absorption and ↑ renal elimination of calcium.
- Denosumab
  MAB which inhibits osteoclast activity. May be indicated for hypercalcaemia of malignancy, where bisphosphonates have failed. Watch for hypocalcaemia.
Procedural
- Parathyroidectomy
  If adenoma.

Complications

Include:

C
- Malignant arrhythmias
F
- AKI
G
- Pancreatitis

Prognosis

Key Studies

References

Shane, Elizabeth, and I. Dinaz. Hypercalcemia: pathogenesis, clinical manifestations, differential diagnosis, and management. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Favus MJ (ed.). Philadelphia: Lippincott, Williams &Wilkins (1999): 183-87.
eviQ. Hypercalcaemia of Malignancy. ID: 486 v.4.
Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.