Calcium Metabolism and
Hypercalcemia
Alex Yartsev
Calcium
• Element number 20
• Makes up 3% of the Earths crust
• Calcium ion: Ca2+
• Divalent cation
Wikipedia
Calcium in the human body
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5th most abundant element in the human body
After cremation, a third of the remaining mass (1kg)
Makes up 70% of hydroxyapatite (Ca10(PO4)6(OH)2)
Most is present in this fixed form: bones and teeth
A little is in the cytoplasm of all the cells
A tiny amount circulates bound to albumin
Miniscule portion is circulating as Ca++ ion
the only physiologically active form is the Ca++ ion
Endocrine Physiology, 3rd ed. P.E. Molina; Chapter 5 (Via CIAP)
Distribution of calcium in the human body
1% of total body calcium is present in the cells
0.1% of total body calcium is in the extracellular fluid:
Ionised Calcium: Ca++
50%
• Present as free, active cation
•Diffuses easily across capillary
membranes
1.2 mmol/L
Hydroxyapatite
98.9%
= 31 mol
= 1250g
Protein-bound Calcium:
41%
1.2 mmol/L
Anion-bound calcium:
9 %, 0.2 mmol/L
1% of which is
available as an
exchangeable pool
• Bound mainly to albumin
•Cannot diffuse across capillary
membranes
• Bound to small anionic
molecules, eg. phosphate and
citrate
• diffuses easily across capillary
membranes
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
What are we measuring, exactly
• CMP calcium from venous blood
– Total calcium: ionized calcium + protein bound +
anion bound; should be 2.2 to 2.6 mmol/L
– Corrected calcium:
• when the albumin is low, protein-bound calcium will also be low;
• however the levels of ionized calcium remain unchanged
• Corrected calcium is what the total calcium WOULD BE if the
patient had a normal albumin level.
– corrected [Ca] in mmol/L =
= measured total [Ca] (mmol/L) + 0.02 x (40 – serum albumin in g/L)
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
What are we measuring, exactly
• ABG calcium:
– Just the ionised fraction
– This is the fraction that is under homeostatic control
– Measured precisely with ion-selective glass electrode
– The most accurate impression of whether
somebody is hypo or hypercalcemic
– Especially in patients on TPN, acidotic patients, ICU
patients with low albumin, patients on dialysis, cases of
hyperparathyroidism, and patients receiving citrated blood
(because citrate binds ionized calcium)
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
McLean et al, Clinical Estimation and Significance of Calcium-Ion Concentrations in the Blood ; Am J Med Sci may 1935 vol. 189:5 pp21-612
Calvi et.al, When Is It Appropriate to Order an Ionized Calcium? 2008 J Am Soc Nephrol 19: 1257-1260, 2008
What is the point of calcium
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Muscle contraction caused by Ca++ efflux from sarcoplasmic reticulum
Neurotransmitter release caused by Ca++ influx into presynaptic terminal
Ca++ instead of Na+
Conduction system of the heart Uses
to depolarise
influx is responsible for the plateau
Myocardial contraction Ca++
phase of the action potential
is a cofactor required at most factor activation steps, that’s why
Clotting cascade Ca++
blood bank purple top tubes contain a calcium chelator (EDTA)
Bone integrity
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
Daily dietary calcium requirements
40 mg = 1 mmol
National Health and Medical Research Council. (2006) Executive Summary of Nutrient Reference Values for
Australia and New Zealand Including Recommended Dietary Intakes.
Commonwealth Department of Health and Aging, Australia, Ministry of Health, New Zealand.
Daily calcium requirements in the ICU
• 0.1 mmol/Kg /day - INTRAVENOUSLY
• Thus, a 100kg ICU pt on TPN needs 10mmol
every day
Oh’s Intensive Care Manual, 6th ed. R.Leonard; Chapter 87 Enteral and parenteral nutrition
Usual Sources of Calcium
• Dairy:
– 200ml yoghurt = 10mmol
– 1 litre of milk = 25 mmol
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Spinach
Baked beans
Oranges
Nuts
Small canned fish with intact bones:
canned sardines = 10mmol per 100g
www.nutritiondata.com
Unusual Sources of Calcium
• Jevity 1cal contains ~23 mmol of calcium per
litre (910 mg)
• One Caltrate tablet = 15 mmol (600mg)
• Calcium resonium: exchanges calcium for
potassium in the gut. Calcium content is 1.6 to 2.4
mmol/g, so each 30g dose = potentially 48 to 72 mmol
• Calcium gluconate: 2.2 mmol per 10ml vial
• Calcium chloride: 6.6 mmol per 10ml vial
http://www.abbottnutrition.ca – Jevity manufacturer
http://www.caltrate.com.au/caltrate-600mg.aspx - Wyeth Consumer Healthcare website
MIMS online via CIAP
Calcium absorption
• NORMALLY, 30-35% of ingested calcium is absorbed
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Thus, to get your 10mmol, you need to ingest ~ 25-30mmol;
Thus, ~ 1 litre of milk or 1.2 litres of Jevity
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Absorption occurs in the duodenum
Active transport out of the gut
Rate of absorption closely linked to calcium demand
Controlling hormone is mainly Vitamin D
(activated vitamin D greatly increases calcium absorption)
• ~ 7 mmol is lost in the intestine as sloughed cells/juices
• NET: 30mmol go in, 27 mmol come out. 3 mmol remain.
• Thus, you only end up keeping 10% of the calcium you ingest
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 65
Calcium transport in the blood
• 50% as ionised, 41% bound to protein (mainly
albumin, some globulins) and 9% bound to anions in
soluble complexes
• Ionized fraction depends on pH:
• protein binding decreases as pH decreases
Alkalosis:
pH 7. 45
pH 7.35
Acidosis:
increased calcium binding to protein;
decreased ionised fraction
Each 0.1 decrease in pH increases
ionized calcium by 0.05 mmol/L
decreased calcium binding to protein;
increased ionised fraction
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
Calcium storage
• 98.9% stored in bone
• 1% stored in cytoplasm and 0.1% is present in the extracellular fluid
• Stored as HYDROXYAPATITE mineral
• Balance of storage is influenced by balance of osteclast vs
osteoblast activity: building vs destruction of the bony matrix
• This is influenced by parathyroid hormone and to a lesser
degree calcitonin
• SHOULD BE NEUTRAL!
• 500mg (12.5mmol) per day should be deposited,
• 500mg (12.5mmol) should be reabsorbed
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
Intestinal calcium excretion
INTESTINAL LOSSES
• 7 mmol (~ 250mg) lost in sloughed cells and intestinal
secretions
• More if there is a vitamin D deficiency
• More if there is hypercalcemia
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
Renal calcium excretion
• 2.5mmol (100mg) is excreted through the kidneys daily
• The ionized calcium is the only excretable variety because
protein-bound calcium does not make it past the glomerulus
• 90% of the filtered calcium is reabsorbed in the proximal
tubule
• The reabsorption of the remaining 10% is controlled by PTH
and depends on ionic calcium concentration
• This remaining 10% is reabsorbed in the early collecting ducts
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 65
Summary of calcium balance
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 65
Calcium homeostasis
Increased
calcium
uptake from
duodenum
and
reuptake in
the nephron
Increased
osteoclast
activity
INCREASED
Ca++ C
Increased
bone
resorption
Sensed by Chief cells in
parathyroid gland
DECREASED PARATHYROID
HORMONE SECRETION
Decreased
osteoclast
activity
Increased
Vitamin D
activation
INCREASED PARATHYROID
HORMONE SECRETION
Decreased
bone
resorption
Sensed by Chief cells in
parathyroid gland
DECREASED
Ca++ C
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
Decreased
Vitamin D
activation
Decreased
calcium
uptake from
duodenum
and
reuptake in
the nephron
Parathyroid hormone
• Secreted by the chief cells of the parathyroid gland
• Secreted in response to decreasing ionized Ca++
• Causes increased osteoclast maturation and thus increased
bone resorption
• Causes increased Vitamin D activation in the kidney
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
Vitamin D
• Lipid soluble vitamin
• Precursors:
– Cholecalciferol in the skin (produced by UV radioation) – Vitamin D3
– Ergocalciferol from diet – Vitamin D2
• Both get hydrolysed in the liver to 25-hydroxyvitamin D3
• Then, in the kidney, get hydrolysed again to 1,25-hydroxyvitamin D
• This last step is under the control of parathyroid hormone
• VITAMIN D ACTIVITY:
– Increased gut absorption of calcium
– Increased reabsorption of calcium in the distal nephron
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
Calcitonin
• Produced by parafollicular cells in the thyroid gland
• Release stimulated by rising ionized calcium levels
• Action:
– directly inhibits osteoclast activity
– Increases renal excretion of calcium by inhibiting resorption
Not critical for calcium homeostasis. Removing the thyroid
causes no major alteration in calcium homeostasis.
Endocrine Physiology, 3rd ed. P.E. Molina; Chapter 5 (Via CIAP)
Hypercalcemia
• Total calcium over 2.6 mmol/L
• Ionized calcium over 1.23 mmol/L
Causes of hypercalcemia
• Excessive PTH
– Primary hyperparathyroidism eg. adenoma, hyperplasia of gland
– Tertiary hyperparathyroidism, eg. long term stimulation of parathyroid gland in
chronic renal failure
– Paraneoplastic PTHrP production (solid tumours)
• Excessive activated Vitamin D
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– Sarcoidosis, silicosis, tuberculosis, lymphomas
– Vitamin D intoxication
Neoplasia, lytic bone lesions
Excessive calcium intake, eg. calcium antacids or TPN
Bone resorption due to immobilization
Hyperthyroidism, antiestrogen therapy, lithium therapy, thiazides
Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL,
Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.
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Consequences of hypercalcemia
HYPERCALCEMIA = NERVOUS SYSTEM DEPRESSION
Reduced reflexes or areflexia
Reduced alertness, depression, confusion, lethargy, coma
Polyuria, polydipsia (reduced concentrating ability)
Bradycardia, AV block, short QT interval, widened T wave
Nausea, anorexia, constipation, abdominal cramps
Bone pain, pathological fractures
Pancreatitis
Peptic ulcers
Renal calculi
Symptoms are usually seen at above 3.0mmol/L
Cardiac arrest is a real possibility at levels above 3.75 mmol/L
Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL,
Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.
Diagnostic aids
• Is it the albumin? Whats the corrected Ca++
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PTH levels, or PTHrP levels
Vitamin D levels
Phosphate and magnesium are done routinely with calcium
What is the renal function
Has anything happened to the neck?
Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL,
Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.
Management of mild hypercalcemia
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Consider not doing anything
Consider stopping calcium replacement
Consider stopping thiazides
Consider giving a different variety of resonium
next time
• Rehydration (hypercalcemia inevitably leads to
dehydration by polyuria)
• Loop Diuretics if volume already normal
Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL,
Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.
Management of severe hypercalcemia
• GOALS:
– Decrease bone resorption
– Increase calcium excretion
– Then, deal with the primary pathology, if possible
Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders
Management of severe hypercalcemia
• Rehydrate aggressively WHILE giving loop diuretics
• Aim for a daily urine output of 4-5 litres
• If there are no kidneys to work with, go with dialysis.
• Infusion of bisphosphonates: pamidronate,
zolendronate, etidronate…
• Takes 1-3 days to reach maximum effect
Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders
Specific strategies
in the management of hypercalcemia
• Chloroquine for sarcoidosis- reduces serum vitamin D levels
• Ketoconazole is also for sarcoidosis-induced hypercalcemia and
vitamin D intoxication
• Hydrocortisone for myeloma, granulomae, Vitamin D intoxication
Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders
Abnormal management of
hypercalcemia
• Gallium Nitrate known to inhibit bone resorption by
altering the structure of hydroxyapatite, equivalent efficacy to
pamidronate but horribly nephrotoxic in 12.5%
• Calcitonin was more popular before bisphosphonates
– For some reason, salmon calcitonin is more powerful than human calcitonin
• Plicamycin (“mithramycin”)- chemotherapy agent, also happens
to lower calcium levels. Pamidronate = more effective, better tolerated
• Disodium Ethylenediaminetetraacetic acid: EDTA
– 15-20mg/kg acts as a calcium chelator, very rapidly lowers
calcium levels;  cardiotoxicity and nephrotoxicity
– Yes it’s the same stuff they put in purple top blood tubes
Time for questions