Hypercalcaemia

OVERVIEW

• highly regulated cation
• involved in: cell death, duration and strength of cardiac muscle contraction, muscle contraction in blood vessels, airways and uterus, coagulation, bone metabolism, neurotransmitter and hormone release…
• Ca²⁺ exists in the extracellular plasma two states:
  1. free ionized state and
  2. bound to other molecules (mostly albumin, rest – beta-globulins, phosphate, citrate)
• ionized Ca²⁺ concentration is inversely related to pH -> an increase in pH results in a decrease in ionized Ca²⁺

Calcium levels

• total Ca²⁺ range = 2.2-2.5mmol/L (55% bound, 45% ionized)
• ionized Calcium range (50%) = 1.1-1.3mmol/L
• protein bound Ca²⁺ range (40%) = 0.95-1.2mmol/L
• complex Ca²⁺ (10% – calcium phosphate, salts) = 0.05mmol/L

CALCIUM METABOLISM

Vitamin D

• group of related sterols
• cholecalciferol is formed in the skin -> in liver to 25-hyrdroxcholecalciferol -> in kidney proximal tubules to 1,25-dihydroxycholecalciferol -> this then helps calcium absorption in the intestine.
• controlled by parathyroid hormone

-> increases intestinal absorption of Ca²⁺
-> increases renal Ca²⁺ reabsorption
-> mobilises bone Ca²⁺ and PO₄³

Parathyroid hormone

• secretion increased by hypocalaemia & hypomagnesaemia
• secretion decreased by hypercalcaemia & hypermagnesaemia

-> mobilses Ca²⁺ from bone
-> increases renal Ca²⁺ reabsorption
-> increases renal PO₄³ excretion
-> increases formation of 1, 25-dihyroxycholecalciferol.

Calcitonin

• antagonist of parathyroid hormone
• secreted by the parafollicular cells of the thyroid gland in response to:
  – hypercalcaemia
  – catecholamines
  – gastrin

-> inhibits the mobilisation of bone Ca²⁺
-> increases renal Ca²⁺ and PO₄^3- excretion

SUMMARY OF CAUSES

• intake: Ca2+, vitamin A or D, hypoMg2+, hypovolaemia, TPN
• redistribution: immobilization, malignancy, hyperparathyroidism, sarcoid, lithium, adrenal insufficiency, endocrine causes (thyrotoxicosis, acromegaly, phaeo)
• output: urinary – thiazides

CAUSES BASED ON FREQUENCY

Common

• malignancy (bone mets, humoral hypercalaemia) -> inappropriate release of PTH-related peptide from tumour cells, associated with lung, breast, prostate, colon and T-cell malignancies and MM
• post-hypocalaemic hypercalcaemia (recovery from pancreatitis, ARF, rhabdomyolysis)
• primary hyperparathyroidism (adenoma)
• adrenal insufficiency
• prolonged immobilisation
• disorders of Mg2+ metabolism
• TPN
• hypovolaemia
• iatrogenic Ca2+ administration

Less Common

• granulomatous disease – sarcoidosis, Tb, beryliosis, leprosy, histoplasmosis -> increase in 1,25(OH)2D production from macrophages in granuloma
• vit A and D intoxification
• endocrine causes: thyrotoxicosis, acromegaly, phaeochromocytoma
• chronic lithium therapy
• secondary hyperparathyroidism (renal failure -> decreased renal conversion of 25-hydroxyvitamin D -> 1,25(OH)2D -> decreased Ca2+ absorption -> increased PTH secretion)
• tertiary hyperparathyroidism (over-activity from prolonged hyperstimulation -> require a parathyroidectomy)

HISTORY

• goal = to quantify severity of hypercalcaemia and find cause (malignancy, diet, immobilisation, medications)
• all symptoms exacerbated by presence of renal failure
• “stones, bones, groans and psychic moans”
• GI – symptoms of smooth relaxation = constipation, anorexia, nausea, vomiting
• NEURO – lethargy, hypotonia, confused, coma
• RENAL – polyuria, dehydration, stones, dehydration
• CVS – arrhythmias

EXAMINATION

• dehydration
• level of consciousness
• exam to find cause (ie. malignancy)

INVESTIGATIONS

(1) to confirm malignancy or bony involvement (x-ray, CT, bone scan)
(2) to assess bone turnover (ALP)
(3) to assess PTH

• U+E – renal failure
• Mg²⁺ and ^K+
• Ca²⁺ and phosphate
• to adjust Ca²⁺ for albumin: add 0.1mmol/L to Ca²⁺ for each 5g/L that albumin below 40g/L
• ECG: shortened QTc, Osborn or J wave
• lipase (can cause pancreatitis)

MANAGEMENT

• quantify severity

Increase Ca2+ Excretion

• N/S IVF @ 200-300mL/hr to promote renal elimination of Ca²⁺
• loop diuretics – decrease resorption of Ca²⁺ in the Loop of Henle
• steroids (hydrocortisone 100mg QID): inhibits the effects of Vit D, decrease intestinal absorption of Ca²⁺, increase renal elimination of Ca²⁺, inhibit osteoclast-activating factor -> useful in granulomatous disease but not in malignancy

Reduce Ca2+ Release

• calcitonin – lowers Ca²⁺ within 24-48 hours
• bisphosphonates (pamidronate 90mg IV) – potent inhibitors of osteoclast activity
• plicamycin and gallium
• inorganic phosphate -> risks Ca2+ precipitation

Others

• stop drugs that might increase Ca2+ (thiazides, vitamin A and D, Ca²⁺)
• restrict intake
• correct K⁺ and Mg²⁺
• mobilize to reduce calcium release from bone
• stop digoxin (hypercalcaemia and digoxin traditionally thought to cause arrhythmia)
• surgery -> parathyroidectomy

VIDEO

Hypercalcaemia by CritIQ:

References and Links

• CCC – Calcium metabolism
• CCC – Calcium basics
• CCC – Hypercalcaemia Overview
• CCC – Hypercalcaemia DDx
• CCC – Hypocalcaemia
• CCC – Hypocalcaemia DDx
• CCC – Calcium replacement (advantages/disadvantages)
• CCC – Calcium as an inopressor